Common targets for a deadly duo of diabetes mellitus and colon cancer: Catching two fish with one worm
Saumitra Gajjar, Bhoomika M. Patel *
A B S T R A C T
Colon cancer is a major health issue and number of cases are increasing every year. Diabetes mellitus is also a significant health issue that is growing day by day worldwide having negative influences on the survival of individuals. Research has shown a strong relationship between the two malignant diseases. The risk of colon cancer with patients who have type 2 diabetes mellitus has spiked by 30%. The scientific research suggests insulin has a major role in the spread of cancer and the condition unifying between the two diseases is hyper- insulinemia. Several anti-diabetic agents are used for the treatment of type 2 diabetesmellitus. However, their mechanism of action against cancer activity is a question and only a few agents have shown positive signs of action in colon cancer associated with type 2 diabetesmellitus. Hence, the identification of targets, which is common for both colon cancer, associated with type 2 diabetesmellitus has become an urgent requirement. Novel targets such as Liver X receptors, Histone deacetylase inhibitors (HDACi), Glucose Transporters (GLUTs), PeroXisome proliferator activator receptors (PPARs), Dipeptidyl peptidase-IV inhibitors (DPP4i), Cyclin- dependent kinase 4 inhibitors (CDK4i), Estrogen receptors,Mechanistic target of rapamycin (mTOR), Insulin- like growth factor receptors (IGF) are some of the targets which are common for both, type 2 diabetesmellitus and colon cancer. This current review gives an overview of the targets (using one worm) which are common for both viz. diabetes mellitus and colon cancer (two fish).
Keywords: Colon cancer HDAC PTP1B
CDK
Estrogen receptor mTOR
1. Introduction
Colon cancer (CRC)is a matter of concern for most countries of the globe and is one of the rapidly increasing types of cancer. Colon cancer is considered one of the common, deleterious disease of the gastrointes- tinal tract associated with high morbidity and mortality. CRC is ranked among the top three carcinomas of the world behind prostate carcinoma and lung carcinoma (Jemal et al., 2010) .In both males and females, CRC is very common and ranks third in terms of its prevalence. Diabetes mellitus (T2DM) is a very serious metabolic disorder in the twenty-first century. T2DMcauses a negative influence in terms of survival and life quality of any individual. According to the International Federation of Diabetes, 1 in 11 adults has diabetes (425 million), and it is estimated that the numbers will increase up to 642 million by 2040 (https://www. cdc.gov/cancer/colorectal/statistics/index.htm, 2018; http://www.dia betesatlas.org/., 2018). T2DM is associated with the three cancers that are pancreatic cancer, breast cancer and lastly CRC (Giovannucci et al., 2010). The molecular mechanism behind diabetes mellitus posing risk to pancreatic cancer is not very well known; however, it is reported that receptors for advanced glycation end products to promote pancreatic cancer tumorigenesis (Kang et al., 2012). Moreover, hyperglycemia enhances local invasiveness, proliferation and metastatis potential in pancreatic cancer (Han et al., 2011). Decrease in estrogen levels sub- sequent to insulin resistance increases the risk of any organ cancer with high levels of estrogen receptors, including breast cancer (Eketunde 2020).
As per various preclinical and clinical data a link has been estab- lished between colon cancer and T2DM that patients increase risk of proXimal or distal CRC which are affected with T2DM (Oh et al., 2008), or colonic as well as rectal cancers (Yang et al., 2005) As per epidemi- ological data, the increase in CRC has reached up to 30% due to diabetes mellitus also with an increase in the number of deaths (Giouleme et al., 2011) A meta-analysis of 24 studies indicated that T2DM is co-related with CRC since there is increased risk of CRC in diabetic patients in comparison with patients with no T2DM (summary RR of colon cancer 1.26, 95% CI 1.20-1.31). Thus, a link between T2DM and CRC has been established and reported in many scientific studies.
CRC and T2DM have various common risk factors such as sedentary lifestyle, junk food, smoking of cigarettes, overweight, visceral adiposity, and hyperinsulinemia. It has been also observed that over- weight, increase in oXidative stress and hyperglycemia also contribute largely to increasing the risk of CRC in diabetes (Giovannucci et al., 2010). Out of several factors, hyperinsulinemia is considered the most important factor of all (Giovannucci, 2001), and insulin therapy was considered to increase the risk of CRC(RR 1.61, 95% CI 1.18-1.35) (Deng et al., 2012). To overcome peripheral insulin resistance there is an increase in insulin production causing insulin levels to rise in T2DM (Yang et al., 2004). In one of the studies, it was shown that prolong insulin treatment in T2DM patients positively correlated with an in- crease in the risk of CRC (Corpet et al., 1997). Studies have also shown that diabetes mediated colon cancer is due to mitochondrial dysfunction (Del Puerto et al., 2019) As well as due to T2DM there occurs damage in the DNA base pairs in colon mucosa which may lead to cancer (Wang et al., 2019) .In a meta-analysis of epidemiological studies of markers associated with hyperinsulinemia and cancer, higher insulin-like growth factor-1 (IGF-1) levels were reported to be associated with an increase in the risk of colorectal adenoma risk (Ors 1.58; 1.16-2.16), thus these reports depicting hyperinsulinemia causes elevation in risk of CRC (Larsson et al., 2005). Insulin is considered to cause cell proliferation when injected in rats, T2DM promoted carcinogen-induced CRC (Lee et al., 2017). Pathway of T2DM leading to CRC is depicted in Fig. 1.
At present various classes of drugs are available to treat T2DMlike- dipeptidyl peptidase 4 inhibitors, biguanides,thiazolidinediones, and sulphonylureas. Several anti-diabetic agents have shown positive results but, their effects to curb cancer are controversial except for metformin. Metformin has shown to exhibit cytotoXic and anti-cancer effects on CRC cell line HCT-15 (Henderson et al., 2017; Meng et al., 2017). As per meta-analysis, metformin has exhibited positive results in CRC (Ioannou and Boyko, 2011); however, many confusing results are associated with the clinical trials (Tran et al., 1996). Hence, the identification of novel targets for both CRC, associated with T2DM has become an urgent requirement.In addition to hyperinsulinemia and insulin-like growth factor, several other pathways contribute to T2DM and CRC. Many novel medicines are under clinical trials individually (Table 120-39 and Table 240-48); however drugs used for both the diseases are not available. The present review shall familiarize readers with the novel targets which are common to both CRC and T2DM (Fig. 2).
2. Common targets for diabetes and colon cancer
2.1. Dipeptidyl peptidase-IV (DPP4)
DPP4 inhibitors belong to the class of oral hypoglycemic agents which blocks the enzyme DPP4. DPP4 is associated with incretin hor- mones GLP-1 (Glucagon-like peptide 1) and GIP (Gastric inhibitory peptide). GLP-1 causes secretion of insulin as it inhibits glucagon on the other hand GIP leads to a decrease in gastric emptying time which collectively decreases blood glucose levels. Both the hormones work in a collective manner (Deacon et al., 1998; Drucker and Nauck, 2007; Gallwitz, 2007). The enzyme DPP4 is importantly associated with the metabolism of glucose; it causes degradation of incretins such as GLP-1 (Barnett, 2006). In comparison with a sulphonylurea, gliptins have shown far better results in reducing the risk of hypoglycemia without altering body weight, along with very low events of adverse reactions and good tolerability (McIntosh et al., 2005).
DPP4 is associated with Fibroblast activation protein (FAP) which is expressed by tumors associated with fibroblasts. FAP is expressed more in CRC thus can be justified that DPP4 has a protective effect against it (Henry et al., 2007). Sitagliptin was found to be more potent than vil- dagliptin on HT-29 tumor cell lines and the IC50 value of Sitagliptin was 32.1 μg/ml and that of vildagliptin was 125 μg/ml using MTT assay proving sitagliptin to be more potent (Amritha et al., 2015).Moreover, the administration of sitagliptin in rats, at doses comparable to those in humans with T2DM, was found to reduce the precancerous lesions and lowered the level of reactive oXygen species in blood (Amritha et al., 2015). In vitro studies showed positive results in CRC for drugs sita- gliptin and vildagliptin. Although the present study was limited by sample size and the observed duration of treatment in the USA, the authors reported that there is no higher short-term pancreatic cancer risk with DPP-4 inhibitor treatment relative to a sulphonylurea or thiazolidinedione treatment (Gokhale et al., 2014). The reason behind it is unclear but a hypothesis has been put forward that activation of GLP receptors causes proliferation of pancreatic acinar and ductal cells causing occlusion of the duct itself. This obstruction produces pressure for the release of digestive enzymes from acinar cells toward the lumen of the occluded duct, therefore causing the onset of pancreatitis, which is an important risk factor for the development of pancreas carcinoma (Butler et al., 2013).
2.2. Peroxisome- proliferator activator receptors (PPARs)
PPARs belong to the class of nuclear receptors complexed with retinoid X receptors. PPARγ a nuclear receptor, which is implicated in adipocyte differentiation and insulin sensitization (Tontonoz et al., 1994), is activated by 15-deoXy-12, 14-prostaglandin J2 (Forman et al., 1995), and by thiazolidinediones (Lehmann et al., 1995; Schoonjans et al., 1997) . On activation,PPARγ increases hepatic glucose output and increases glucose uptake into the muscle by enhancing the effect of insulin.
Scientific studies have suggested the role of PPARγ in cell cycle regulation by altering cell cycle regulatory proteins and cellular differentiation in colonic epithelium, suggesting its antineoplastic effect (Burton et al., 2008; Cesario et al., 2006; Osawa et al., 2003; Thompson, 2007). As it is involved in differentiation, PPARγ also serves as a target for cancerous conditions (Tontonoz et al., 1997). Overexpression of PPARγ has been observed in many tumor conditions like liposarcomas, CRC, breast, and pancreatic carcinomas (Cannata et al., 2010). PPARγ expression has been examined in human CRC tissue (Gustafsson et al., 2007; Konstantinopoulos et al., 2007; Theocharis et al., 2007) .Activation of PPARγ by prostaglandins and fatty acids and high levels are expressed in large intestines in animals and humans (Fajas et al., 1997; Mansen et al., 1996). PPARγ is also found to be activated by omega 3 fatty acids which have resulted in a decrease of CRCprogression in many in vivo models (Iigo et al., 1997; Takahashi et al., 1994). and have also been found to cause a reduction in cellular proliferation rated in colo- rectal mucosa of patients which are having familial adenomatous pol- yposis (Beck et al., 1991).
2.3. Insulin like growth FACTOR-1 (IGF-1)
IGF-1 and insulin growth factor relative binding (IGFBP) protein play a part in cell growth, proliferation, metabolism, apoptosis (Deng et al., 2012). IGFBP-1 binds with IGF-1 which causes a reduction in the free circulating IGF-1levels in the body thus lowering glucose and main- taining its level. IGFBP-1 also plays an important role in apoptosis and cell proliferation (Sridhar and Goodwin, 2009). In T2DM, high levels of insulin promote IGF-1 biosynthesis, which increases the IGF-1 levels which in turn causes inhibition of IGFBP-1, IGFBP-2, and IGFBP-3 (Sakai et al., 2001). IGFBP-1 alters IGF-1 by undergoing serine phosphorylation and enhancing its affinity for IGF-1 which causes to inhibit IGF-1 actions (Sandhu et al., 2002). In cancer conditions there occurs an increase in free IGF-1 in blood and bind to its respective receptors which are expressed in colorectal epithelia. As a result of binding there occurs inhibition of apoptosis which allows cell proliferation with the help of cell cycle (Sekharam et al., 2003).Thus, the accumulation of IGF-1 leads to an increase in cellular turnover resulting in colorectal carcinogenesis. In the HCT116 cell line, overexpression of IGF-1 receptors was re- ported (Dunn et al., 1997). In murine models, the administration of IGF-1 resulted in high invasive tumor and production of distant metas- tasis (Wu et al., 2003). Transgenic mice with liver-specific IGF-1 defi- ciency (LID) had a decrease in growth and metastasis of transplanted colonic adenocarcinomas (Wu et al., 2002). In both LID mice with ncolonic adenocarcinomas, IGF-1 caused an increase in tumor growth and worsened the condition (Major et al., 2010).In Rancho Bernardo’s study, after eighteen years, follows up, subjects with IGF-1 levels of above 100ng/ml had a risk of CRC death that is 1.82 in comparison to those having levels of IGF-1 that is above 200 ng/ml were having 2.61 (Major et al., 2010). Thus, IGF-1 is implicated in the future for both T2DM as well as CRC. The link between IGF-1 and CRC has been depicted in Fig. 3.
2.4. Liver X receptors (LXRs)
Liver X receptors are nuclear receptors that are oXysterol activated and play a major role in triglyceride and cholesterol metabolism. LXRα is present in regions such as intestines, adipose tissue, liver, macrophages, and kidneys whereas LXRβ is expressed almost everywhere (Tontonoz and Mangelsdorf, 2003).LXR activation causes improvement in insulin sensitivity and normalizes glycemia in rodent models of T2DM and in- sulin resistance (Tontonoz and Mangelsdorf, 2003). LXRs regulate in- testinal absorption and biliary excretion of cholesterol by activating target genes like ATP binding cassette (ABC) transporters ABCA1, ABCG5, and ABCG8.
LXRs are expressed in different carcinomas such as prostate breast carcinoma and CRC and play part in proliferation and death of a cell in vitro and vivo (Fukuchi et al., 2004; Vedin et al., 2009). LXR activation causes suppression of β catenin transactivation by direct interaction which inhibits cellular proliferation in CRC (Uno et al., 2009). Apart from β catenin, LXRs also induce CRC cell death through caspase 1 activation. LXR agonists induce ATP release through direct interaction with pannexin-1 and LXRβ (Lo Sasso et al., 2013), this ATP causes activation of purinergic receptor P2-7, due to which caspase-1 activation occurs which eventually causes pyroapoptosis (Kaneko et al., 2003). The biggest drawback of LXRs is that it causes an increase in the triglyceride levels which may increase the chances of hepatic steatosis (Schultz et al., 2000).Overcoming this drawback by designing novel compounds LXRs can prove to be a future potential target for the deadly duo.
2.5. Estrogen receptors
Estrogen receptors come under the class of nuclear receptors. Es- trogen bind to two important receptors (ESRs) the first being the ESRα and second being ESRβ. Estrogen receptors are associated with osteoporosis, obesity, cardiovascular and neurodegenerative disorders. Nowadays its role is being explored in T2DM and cancers like breast, ovary, uterus, and lung and CRC (Ascenzi et al., 2006; Burns and Korach, 2012; Thomas and Gustakfsson, 2011) .ESRα and ESRβ are associated with T2DM; they cause phosphorylation of ERK1/2 pathway which plays role in insulin biosynthesis, insulin secretion, and β-cell survival as it controls glucose homeostasis. ESRβ regulates insulin action through actions on insulin-sensitive tissues or indirectly by regulating oXidative stress which contributes to insulin resistance (Deroo and Korach, 2006). In skeletal muscles, ESRα is thought to have a positive effect on insulin signaling and GLUT 4 expression whereas ESRβ may be prodiabetogenic and cause reduced GLUT 4 expression along with reduced expressions of TNFα, lipoprotein lipase, and fatty acid synthase. ESRβ also regulates pancreatic β cell functions through ESRα mechanism. ESRα knockout mice have increased susceptibility to oXidative stress causing precipi- tation of β cell apoptosis (Barros et al., 2009).The protective effect ESRβ on β cells are primarily nongenomic and likely independent of ESRs since 17α-estradiol also mimics the same effect (Barros et al., 2009). All these suggest that ESRβ influences glucose metabolism along with ESRα. ESRβ is a predominant receptor which is present in normal as well as malignant colonic epithelium. There is a decrease in the expression of ESRβ in colonic tumorigenesis. This can also be used to grade cancer (Jordan, 2007).This also proves that the receptor is having an inverse relationship with the condition. In vitro studies reveal estrogen stimu- lation leading to an increase in ESRβ expression which causes rein- forcement of pro-apoptotic signaling in CRC. It causes caspase-dependent apoptosis (Syed et al., 2001). It causes inhibition of inflammatory signals by inhibition of TNF-α, interleukin 6. It causes cell cycle arrest and lastly modulates tumor microenvironment (Cvoro et al., 2008).Women who took Hormone replacement therapy for 5.6 years had 44% lower risk of CRC compared with nonusers, this was the only positive feedback regarding cancer-related women’s health initiative finding on HRT (Hartman et al., 2006).These facts suggest that a pan modulator can be designed which can be effective in both T2DMas well as CRC.
2.6. mTOR pathway
The mechanistic target of rapamycin is mTOR which is serine/ threonine-protein kinase. The main function of mTOR is triggering biosynthesis of protein and increasing cell turnover. mTOR functions as protein tyrosine kinase which promotes activation of insulin receptors and IGF-1 receptors thus playing an important role in T2DM. Activation of mTOR causes the secretion of insulin and increases insulin sensitivity (Shah et al., 2004). Over activation of the mTOR pathway causes insulin resistance. A study has shown that liraglutide protects renal damage in diabetic rats with kidney disease via AktmTOR pathway (Tzatsos and Kandror, 2006) mTOR causes activation of S6 kinase (S6K), which in turn causes phosphorylation and degradation of insulin receptor sub- strate 1/2 which impairs insulin signaling (Khamzina et al., 2005; Liao et al., 2019; Tremblay et al., 2005, 2007)
Activation of mTOR due to a mutation in the mTOR gene has been observed in cancerous condition (Barbour et al., 2011; Saha et al., 2011).There occurs over activation of the mTOR pathway as a result of a defect in the phosphatidylinositol 3 kinase (PI3K/Akt/mTOR) pathway. PI3K pathway mutations are generally found in late tumorogenesis and can be identified in 32% of CRC tumors (Dalgliesh et al., 2010). Loss of heterozygosity and mutations in phosphatase and tensin homolog (PTEN) which is a negative regulator of PI3K activity has been reported in CRC (Robbins, 2011). PI3K mutation and PTEN loss leads to over activation of mTOR (Samuels et al., 2004). Due to somatic missense mutation of Akt1, its prolonged activation has also been observed in CRC which eventually leads tothederegulation of mTOR (Zhou et al., 2002). Continuous treatment with novel rapamycin formulation delayed cancer in tumor prone p53 /- and p53-/- mice by slowing down their aging process (Carpten et al., 2007; Soung et al., 2006). Inhibition of mTORcan lead to improving conditions by intestinal regeneration in patients with intestinal atrophy (Comas et al., 2012). Ex vivoimmunohistochemical studies in human colorectal adenomas and cancer confirmed mTORC1 signaling occurs as an early event in the process of tumorigenesis (Komarova et al., 2012). Everolimus has a high affinity for FK506 binding protein making it a more specific inhibitor of mTORC1. This inhibition leads to a blockage in the progression of cells from the G1 phase of the cell cycle into S phase, and as a result, induces cell growth arrest and apoptosis (Aoki et al., 2003).Everolimus mediated mTORC1 inhibition suppressed polyp formation and reduced mortality in Apc716 mice (ArriolaApelo et al., 2016; Warburg, 1956). Maslinic acid has shown positive results in CC via AMPK-mTORsignalling pathway (Wei et al., 2019; Zhang et al., 2009) mTOR antagonists are useful for T2DM and CRC. Hence, common modulator who can control both the condi- tions can be designed.
2.7. Glucose transporters (GLUTs)
GLUTs are integral membrane proteins which provide facilitated diffusion of glucose. Cells obtain glucose by glucose transporters. In the diabetic state there occurs deregulation of these transporters. There are many glucose transporters such as GLUT1, GLUT2, etc, in the cells which regulate the glucose levels in the blood, but GLUT4 is the only GLUT that responds to insulin (Flier et al., 1987). Overexpression of GLUT1 re- ceptors worsens the diabetic condition by increasing glucose conditions. Cancerous cells have increased consumption of glucose; the whole process is based on the fermentative pathway with lactic acid produc- tion. OXidative catabolism is impaired in cancer cells (Flier et al., 1987). GLUT1 overexpression has shown tumor progression in CRC sug- gesting GLUT1 as an important biomarker for depicting cancer (Haber et al., 1998).Also overexpression shows an increase in glucose uptake in CRC (Haber et al., 1998). In CRC cell lines mutations in KRAS (Kirsten rat sarcoma viral Oncogene homolog) or BRAF (vraf murine sarcoma viral oncogene homolog B1) genes cause overexpression of GLUT1 (Yun et al., 2009). In CRC cell line Caco-2, transfection with rasor the poly- oma middle T oncogene caused an increase in expressions of GLUT1, GLUT3, which have high affinities for glucose, but repressed expressions of GLUT2 and GLUT5, which have lower affinities for glucose (Baron– Delage et al. 1996). Transfected Caco-2 cells also have an increased rate of glucose consumption (Baron-Delage et al. 1996). This proves that the upregulation of GLUT1 and GLUT3 occurs in cancer state, so targeting GLUT1, GLUT3 as well as GLUT4 a modulator acting on GLUT1, GLUT3, and GLUT4 is needed which can control both diabetes and CC.
2.8. Protein tyrosine phosphatase 1B (PTP1B)
Protein tyrosine phosphatase group of enzymes that remove phos- phate groups from phosphorylated tyrosine residues on proteins. PTP1B enzymes are key regulatory components in signal transduction pathways (MAP kinase pathway) and the cell-cycle, growth, proliferation, differ- entiation, transformation, and synaptic plasticity (DiXon and Denu, 1998; Goebel-Goody et al., 2012; Paul and Lombroso, 2003; Tonks et al., 2006; Zhang et al., 2010) .The PTPs constitute a huge family of enzymes with 107 members into 4 different groups Class 1, II, III, IV based on their protein sequences and functions (Alonso et al., 2004; Elchebly et al., 1999) . These enzymes are found to control the degree of signaling with Src pathway. PTP1B comes under Class 1 of the PTP family. In T2DM, in adipocytes, a higher concentration of lipids causes dephos- phorylation of tyrosyl residues leading to lipid deposition causing hin- drance in glucose uptake thus proving PTP1B as a negative regulator in diabetes signaling (Dadke and Chernoff, 2003). A study has revealed that selective deficiency in PTP1B protects from diabetic complications (Legeay et al., 2020) PTP1B down-regulates insulin signaling by directly dephosphorylating insulin receptor and insulin receptor substrates. PTP1B antibodies have shown to increase insulin receptor phosphory- lation suggesting that PTP1B inhibition could sensitize insulin (Arregui et al., 1998).
PTP1B is found to cause dephosphorylation of various other growth factors such as endothelial growth factor (EGF); platelet-derived growth factor (PDGF) and insulin receptors, as well as cytoplasmic kinases like Src and Janus, activated kinase (JAK) (Tonks et al., 2006). Over- expression of PTP1B has been observed in CRC. Src kinase activity is elevated in a very high proportion of human CRC cell lines and this elevation has been shown to promote tumorigenicity of CRC cells (Balavenkatraman et al., 2011). Thus, PTP1B can serve as an important prognostic biomarker in CRC patients (Krishnan et al., 2014; Zhu et al., 2007) .It has been suggested that PTP1B has a positive regulatory role in Ras activity and founded upregulation of p120 RasGTPase activating protein (p120RasGAP, RASA-1) in PTP1B deficient fibroblasts (Kolfschoten et al., 2005; Queting et al., 2014) .By dephosphorylating PITX-1 (Paired like homeodomain-1), the transcription factor of p120RasGAP, PTP1B destabilizes PITX-1 protein which leads to down-regulation of p120RasGAP to promote the proliferation of CRC cells (Hoekstra et al., 2016). Thus PTP1B inhibitors are of great interest to be explored in insulin receptor signaling and colon carcinogenesis.
2.9. Histone deacetylase (HDAC)
HDAC catalyzes the deacetylation of lysine residues which are bound inside the DNA core histone proteins (Sealy and Chalkley, 1978). The enzyme’s way of working is opposite to histone acetyltransferase (HATs) which catalyzes lysine acetylation (Sealy and Chalkley, 1978). Their role in T2DM is under study; they control insulin synthesis and its release by increasing AMPK (5- adenosine monophosphate-activated protein kinase) activator (Sealy and Chalkley, 1978). In addition to improving insulin resistance and prevention of β-cell inflammatory damage, there is evidence of a link between T2DM and HDACs. HDAC inhibitors pro- mote β-cell development, proliferation, and positively affect diabetic micro-vascular complications (Lopez Rodas et al., 1993).They also control CV complications associated with T2DM (Kuo and Allis, 1998; Patel et al., 2014; Patel, 2018; Rabadiya et al., 2018)
HDAC overexpression causes repression of genes that function nor- mally in growth arrest, differentiation, and cell death by causing histone hypoacetylation (Raghunathan et al., 2017). HDAC inhibitors cause apoptosis in the colon. They bring cell differentiation, cause induction of growth inhibitory genes like p21 (Kim et al., 1980), HDAC inhibitors also co-ordinate with various cyclins, CDKs, and various transcriptional factors. They control and regulate cell cycle progression, including myc, myb and several E2F family members (Hague et al., 1993). The colo- rectal cancer cells express wild type Adenomatous polyposis coli (APC) yet they have resistance against the apoptotic effect of HDACi. APC expression is an important requirement for HDAC inhibitor-induced down-regulation of survivin, which sensitizes cells to apoptosis (Mariadason et al., 2000). The class I HDACs which consist of HDAC1, HDAC2, HDAC3, and HDAC8 are found to be overexpressed in CRC (Huang and Guo, 2006). The pro-proliferative effects of HDACs are connected to the transcriptional repression of CDK-inhibitor, p21, and knockdown of HDAC1, HDAC2, and HDAC3 cause reduction in CRC cells (Mariadason, 2008). Thus proving HDACs may serve as potential targets in CRC; Vorinostat inhibits the enzymatic activity of histone deacety- lases HDAC1, HDAC2, and HDAC4. It acts as a chelator for zinc ions which are present in histone deacetylases. As a result of Vorinostat in- hibition there occur the accumulation of acetylated histones and pro- teins as a result of which there is cell cycle arrest (Wilson et al., 2010). It is the first approved HDACi for cutaneous T cell lymphoma is at present in phase 2 clinical trials for colorectal cancer. Trichostatin A is also understudies for CC (Marks and Dokmanovic, 2005). EXpression of HDAC2 in CRC cell lines showed to be promoted by TCF-Myc signaling which is the fundamental pathway deregulated in CC (Heerdt et al., 1997). Treatment of CRC cells with HDACi induced G0/G1 growth arrest within 12–16 h (Heerdt et al., 1994). Recently, HDAC inhibitor sodium valproate has been reported to be beneficial in diabetes-associated CRC (Patel and Patel., 2018). Thus, HDAC inhibitors can be considered as potential targets in the future for colorectal cancer associated with T2DM.
2.10. Cyclin dependent kinases (CDKs)
The cyclin-dependent kinases (CDKs) are serine/threonine protein kinases. It consists of small proteins that are composed of catalytic core shared by various protein kinases. The most important part is the requirement of regulatory subunit proteins known as cyclins which are required for propagation of CDK activity. Cyclins along with CDKs play a regulatory role multiplication of cells. Though CDKs levels remain the same, their activity keeps on varying and is dependent on the amount of phosphorylation that occurs. CDK4 plays an important role in glucose metabolism. In T2DM there is abnormal hyperglycemia due to abnormal production of insulin which causes resistance of insulin along with hyperinsulinemia (Fajas et al., 2010). Hyperinsulinemia causes β-cell proliferation again leading to increase levels of insulin which may develop resistance rendering oral hypoglycemic agents ineffective (Alonso et al., 2004). Different studies have reported that CDK4 causes an increase in β-cell proliferation (Cordain et al., 2003; Cozar-Castellano et al., 2004).
Palbociclib is a CDK4 and CDK6 inhibitor by which it inhibits the formation of cyclinD-CDK4/6 complex as a result of which cell cannot pass from Restriction point (G1/S phase checkpoint) which eventually reduces β-cells proliferation (Abella et al., 2005; Fatrai et al., 2006; Hanxiao et al., 2017; Sacaan et al., 2017) .Similarly, in another study, IDCX another CDK4 inhibitor has shown to increase basal glucose up- take and increase in GLUT1 mRNA levels in 3T3-L1 adipocyte cell lines (Malumbres and Barbacid, 2009). Thus, CDK4 contributes in T2DM by regulating β-cells and their proliferation.
A variety of genetic and epigenetic responses in cancer cells is responsible for the overexpression of CDKs. Due to the deregulation of CDKs cancerous cells undergo unscheduled proliferation and there also occurs chromosomal instability (Shapiro, 2006). Most common are the CDK4/6 and cyclin D in human cancer cells (Harbour and Dean, 2000). CDK4/6 both are activated by cyclins (D1, D2, D3) and they act on the G1 phase of cell cycle causing initiation of DNA synthesis. Cyclin D-CDK4/6 complex partially causes phosphorylation of retinoblastoma tumor suppressor protein (Rb). Inhibition of Rb protein causes the production of some genes important in the progression of the S phase (Vermeulen et al., 2003). The complex formed results into hyper- phosphorylation of Rb causing it to get separated from the Rb-E2F complex causing E2F active (Fry et al., 2004). Thus, by CDK inhibitors the uncontrolled proliferation of cancer cells can be controlled. Palbo- ciclib is a selective CDK4/6 inhibitor which is approved for breast cancer is in the third phase of trials for colorectal carcinoma. Palbociclib caused an inhibition of proliferation of tumor cell lines that retain functional Rb, it blocks its phosphorylation on CDK4 and CDK6 sites. CC cell lines treated with CDK4 inhibitor palbociclib exhibited loss of proliferation marker Ki67 and caused downregulation of E2F target genes (IC50 values for cultured cells: 40 to 170 nmol/L) (Toogood et al., 2005). In many Xenograft models, Palbociclib was effective in inhibiting tumor growth and regression was tolerated without significant toXicities at daily doses to 150mg/kg for up to 50 days of treatment (Patel and Shah, 2016). In a recent study Palbociclib has also shown improvement in cardiac dysfunction in diabetic cardiomyopathy by regulating Rb phosphorylation (Z. Wang et al., 2019) Moreover, CDK4 inhibition is also reported to play a beneficial role in diabetic CC (ArriolaApelo et al., 2016). A summary of common targets for the deadly duo is depicted in Fig. 4.
3. Conclusions
Diabetic patients are more prone to develop colon cancer. With the increasing population of patients suffering from diabetes more patients with colon canceris likely to increase. The current treatment approach for diabetes is focused on bringing tight glucose control and prevents long time diabetic complications. Advancements in the field of molec- ular biology have led to an improved understanding of the common targets and pathways, which regulate glucose homeostasis and cellular proliferation and novel targets for individual diseases are now known (Mehta and Patel, 2019). Since type 2 diabetes mellitus and colon cancer share several common risk factors, acting on such risk factors should be the prime approach. Also, future research should focus on developing therapies that can act on both type 2 diabetes mellitus and colon cancer prevention or treatment. The novel agents could either be pure agonists or antagonists acting at the common target. Alternatively, for targets like IGF1, mTOR, HDACi pan agonists, or modulators can be developed which act as agonists at
development of such important targeted therapies brings a positive JSH-150 hope for the patients to control the deadly duo by using one worm to catch hold of the two fish!
References
Abella, A., Dubus, P., Malumbres, M., Rane, S.G., Kiyokawa, H., Sicard, A., Vignon, F.,
Langin, D., Barbacid, M., Fajas, L., 2005. Cdk4 promotes adipogenesis through PPAR gamma activation. Cell Metabol. 2, 239–249.
Alonso, A., Sasin, J., Bottini, N., Friedberg, I., Friedberg, I., Osterman, A., Godzik, A., Hunter, T., DiXon, J., Mustelin, T., 2004. Protein tyrosine phosphatases in the human genome. Cell 6, 699–711.
Amritha, C.A., Kumaravelu, P., Chellathai, D.D., 2015. Evaluation of anti cancer effects of dpp-4 inhibitors in colon cancer- anIn vitro study. J. Clin. Diagn. Res. 9 (14–6), 1247–1256, 16.
Aoki, K., Tamai, Y., Horiike, S., Oshima, M., Taketo, M.M., 2003. Colonic polyposis caused by mTOR-mediated chromosomal instability in Apc /Delta716 Cdx2 /- compound mutant mice. Nat. Genet. 35, 323–330.
Arregui, C.O., Balsamo, J., Lilien, J., 1998. Impaired integrin mediated adhesion and signaling in fibroblasts expressing a dominant-negative mutant PTP1B. J. Cell Biol. 143, 861–873.
ArriolaApelo, S.I., Neuman, J.C., Baar, E.L., Syed, F.A., Cummings, N.E., Brar, H.K., Pumper, C.P., Kimple, M.E., Lamming, D.W., 2016. Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system. Aging Cell 15 (1), 28–38.
Ascenzi, P., Bocedi, A., Marino, M., 2006. Structure-function relationship of estrogen receptor alpha and beta: impact on human health. Mol. Aspect. Med. 27, 299–402. Balavenkatraman, K.K., Aceto, N., Britschgi, A., Mueller, Urs, Bence Kendra, K., Neel, B.,
Bentires-Alj, M., 2011. Epithelial protein- tyrosine phosphatase 1B contributes to the induction of mammary tumors by HER2/neu but is not essential for tumor maintenance. Mol. Canc. Res. 9, 1377–1384.
Barbour, L.A., McCurdy, C.E., Hernandez, T.L., Friedman, J.E., 2011. Chronically increased S6K1 is associated with impaired IRS1 signaling in skeletal muscle of GDM women with impaired glucose tolerance postpartum. J ClinEndocrinolMetab 96, 1431–1441.
Barnett, A., 2006. DPP-4 inhibitors and their potential role in the management of type 2 diabetes. Int. J. Clin. Pract. 60, 1454–1470.
Baron-Delage, S., Mahraoui, L., Cadoret, A., Veissiere, D., Taillemite, J.L., Chastre, E., Gespach, C., Zwebaum, A., Capeau, J., Brot-Laroche, E., Cherqui, G., 1996.
Deregulation of hexose transporter expression in Caco-2 cells by ras and polyoma middle T oncogenes. Am. J. Physiol. 270 (2 Pt 1), G314–G323.
Barros, R.P.A., Gabbi, C., Morani, A., Warner, M., Gustafsson, J.A., 2009. Participation of ERα and ERβ in glucose homeostasis in skeletal muscle and white adipose tissue. Am J PhysiolEndocrinMetab 297, E124–E133.
Beck, S.A., Smith, K.L., Tisdale, M.J., 1991. Anticachectic and antitumor effect of eicosapentaenoic acid and its effect on protein turnover. Can. Res. 51, 6089–6093.
Burns, K.A., Korach, K.S., 2012. Estrogen receptors and human disease: an update. Arch. ToXicol. 86, 1491–1504.
Burton, J.D., Goldenberg, D.M., Blumenthal, R.D., 2008. Potential of peroXisome proliferator-activated receptor gamma antagonist compounds as therapeutic agents for a wide range of cancer types. PPAR Res. 494161. phosphatase+1+B&cond=Type+2+Diabetes+Mellitus&rank=1. (Accessed 22 June 6.00pm. https://clinicaltrials.gov/ct2/show/NCT00162240?term PPARs&cond Type Receptors&cond Type 2 Diabetes Mellitus&rank 1, accessed on 22nd June, 2020, 6.00pm. https://clinicaltrials.gov/ct2/show/NCT01242228?term dpp4 inhibitors&cond Type
Cordain, L., Eades, M.R., Eades, M.D., 2003. Hyperinsulinemic diseases of civilization: more than just Syndrome X. Comp BiochemPhysiolAMolIntegrPhysiol 136, 95–112.
Corpet, D.E., Jacquinet, C., Peiffer, G., Tache, 1997. Insulin injections promote the growth of aberrant crypt foci in the colon of rats. Nutr. Canc. 27, 316–320.
Cozar-Castellano, I., Takane, K.K., Bottino, R., Balamurugan, A.N., Stewart, A.F., 2004. Induction of beta-cell proliferation and retinoblastoma protein phosphorylation in rat and human islets using adenovirus-mediated transfer of cyclin-dependent kinase- 4 and cyclin D1. Diabetes 53, 149–159.
Cvoro, A., Tatomer, D., Tee, M.K., Zogovic, T., Harris, H.A., Leitman, D.C., 2008. Selective estrogen receptor-beta agonists repress transcription of proinflammatory genes. J. Immunol. 180, 630–636.
Dadke, S., Chernoff, J., 2003. Protein-tyrosine phosphatase 1B mediates the effects of insulin on the actin cytoskeleton in immortalized fibroblasts. J. Biol. Chem. 278, 40607–40611.
Dalgliesh, G.L., Furge, K., Greenman, C., et al., 2010. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 463, 360–363.
Deacon, C.F., Hughes, T.E., Holst, J.J., 1998. Dipeptidyl peptidase IV inhibition potentiates the insulinotropic effect of glucagon-like peptide 1 in the anesthetized pig. Diabetes 47, 764–769.
Del Puerto, N.L., Santiago, H.A., Solanes, C.S., Gonzalez, N., et al., 2019. Diabetes- mediated promotion of colon mucosa carcinogenesis is associated with mitochondrial dysfunction. DiabetesCancerConnectConsortium.MolOncol. 13 (9), 1887–1897.
Deng, L., Gui, Z., Zhao, L., 2012. Meta-analysis RA´. Diabetes mellitus and the incidence of colorectal cancer: an updated systematic review and meta-analysis. Dig. Dis. Sci. 1576–1585.
Deroo, B.J., Korach, K.S., 2006. Estrogen receptors and human disease. J. Clin. Invest. 116, 561–570. http://www.diabetesatlas.org/. (Accessed 28 December 2018).
DiXon, J.E., Denu, J.M., 1998. Protein tyrosine phosphatases: mechanisms of catalysis and regulation. Curr. Opin. Chem. Biol. 2, 633–641.
Drucker, D.J., Nauck, M.A., 2007. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 368, 1696–1705.
Dunn, S.E., Kari, F.W., French, J., et al., 1997. Dietary restriction reduces insulin-like growth factor I levels, which modulates apoptosis, cell proliferation, and tumor progression in p53-deficient mice. Can. Res. 57, 4667–4672.
Eketunde, A.O., 2020. Diabetes as a risk factor for breast cancer. Cureus 12 (5), e8010. Elchebly, M., Payette, P., Michaliszyn, E., et al., 1999. Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science 83, 1544–1548.
Fajas, L., Auboeuf, D., Rasp´e, E., et al., 1997. Organization, promoter analysis and expression of the human PPARg gene. J. Biol. Chem. 272, 18779–18789.
Fajas, L., Blanchet, E., Annicotte, J.S., 2010. CDK4, pRB and E2F1: connected to insulin. Cell Div. 5, 6.
Fatrai, S., Elghazi, L., Balcazar, N., et al., 2006. Akt induces beta-cell proliferation by regulating cyclin D1, cyclin D2, and p21 levels and cyclin-dependent kinase-4 activity. Diabetes 55, 318–325.
Flier, J.S., Mueckler, M.M., Usher, P., Lodish, H.F., 1987. Elevated levels of glucose transport and transporter messenger RNA are induced by ras or srconcogenes. Science 235 (4795), 1492–1495.
Forman, B.M., Tontonoz, P., Chen, J., et al., 1995. 15-DeoXy-D12,14 prostaglandin J2 is a ligand for the adipocyte determination factor PPARγ. Cell 83, 803–812.
Fry, D.W., Harvey, P.J., Keller, P.R., et al., 2004. Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor Xenografts. Mol. Canc. Therapeut. 3, 1427–1438.
Fukuchi, J., Kokontis, J.M., Hiipakka, R.A., et al., 2004. Antiproliferative effect of liver X receptor agonists on LNCaP human prostate cancer cells. Can. Res. 64, 7686–7689.
Gallwitz, B., 2007. Sitagliptin with metformin: profile of a combination for the treatment of type 2 diabetes. Drugs Today (Barc). 43, 681–689.
Giouleme, O., Diamantidis, M.D., Katsaros, M.G., 2011. Is diabetes a causal agent for colorectal cancer? Pathophysiological and molecular mechanisms. World J. Gastroenterol. 17, 444–481.
Giovannucci, E., 2001. Insulin, insulin-like growth factors and colon cancer: a review of the evidence. J. Nutr. 131, 3109–3120.
Giovannucci, E., Harlan, D.M., Archer, M.C., et al., 2010. Diabetes and Cancer: a consensus report. Diabetes Care 33, 1674–1685.
Goebel-Goody, S.M., Wilson-Wallis, E.D., Royston, S., et al., 2012. Genetic manipulation of STEP reverses behavioral abnormalities in a fragile X syndrome mouse model. Gene Brain Behav. 11, 586–600.
Gokhale, M., Buse, J.B., Gray, C.L., et al., 2014. Dipeptidyl-peptidase-4 inhibitors and pancreatic cancer: a cohort study. Diabetes Obes. Metabol. 16, 1247–1256.
Gustafsson, A., Hansson, E., Kressner, U., et al., 2007. EP1-4 subtype, COX and PPAR gamma receptor expression in colorectal cancer in prediction of disease-specific mortality. Int. J. Canc. 121, 232–240.
Haber, R.S., Rathan, A., Weiser, K.R., et al., 1998. GLUT1 glucose transporter expression in colorectal carcinoma: a marker for poor prognosis. Cancer 83 (1), 34–40.
Hague, A., Manning, A.M., Hanlon, K.A., et al., 1993. Sodium butyrate induces apoptosis in human colonic tumor cell lines in a p53-independent pathway: implications for the possible role of dietary fibre in the prevention of large bowel cancer. Int. J. Canc. 55, 498–505.
Han, L., Ma, Q., Li, J., Liu, H., Li, W., Ma, G., Xu, Q., Zhou, S., Wu, E., 2011. High glucose promotes pancreatic cancer cell proliferation via the induction of EGF expression and transactivation of EGFR. PloS One 6 (11), e27074.
Hanxiao, X., Shengnan, Y., Qian, L., et al., 2017. Recent advances of highly selective CDK4/6 inhibitors in breast cancer. J. Hematol. Oncol. 10 (1), 97.
Harbour, J.W., Dean, D.C., 2000. The Rb/E2F pathway: expanding roles and emerging paradigms. Gene Dev. 14, 2393–2409.
Hartman, J., Lindberg, K., Morani, A., et al., 2006. Estrogen receptor β inhibits angiogenesis and growth of T47D breast cancer xenografts. Can. Res. 66, 11207–11213.
Heerdt, B.G., Houston, M.A., Augenlicht, L.H., 1994. Potentiation by specific short-chain fatty acids of differentiation and apoptosis in human colonic carcinoma cell lines. Can. Res. 54, 3288–3293.
Heerdt, B.G., Houston, M.A., Augenlicht, L.H., 1997. Short-chain fatty acid-initiated cell cycle arrest and apoptosis of colonic epithelial cells is linked to mitochondrial function. Cell Growth Differ. 8, 523–532.
Henderson, D., Frieson, D., Zuber, J., Solomon, S.S., 2017. Metformin has positive therapeutic effects in colon cancer and lung cancer. Am. J. Med. Sci. 354, 246–251.
Henry, L.R., Lee, H.O., Lee, J.S., et al., 2007. Clinical implications of fibroblast activation protein in patients with colon cancer. Clin. Canc. Res. 13, 1736–1741.
Hoekstra, E., Das, A.M., SwetsM, et al., 2016. Increased PTP1B expression and phosphatase activity in colorectal cancer results in a more invasive phenotype and worse patient outcome. Oncotarget 7, 21922–21938.
Huang, X., Guo, B., 2006. Adenomatous polyposis coli determines sensitivity to histone deacetylase inhibitor induced apoptosis in colon cancer cells. Can. Res. 66,9245–9251.
Iigo, M., Nakagawa, T., Ishikawa, C., et al., 1997. Inhibitory effects of docosahexaenoic acid on colon carcinoma 26 metastasis to the lung. BrJ Cancer 75, 650–655.
Ioannou, G.N., Boyko, E.J., 2011. Metformin and colorectal cancer risk in diabetic patients. Diabetes Care 34, 2336–2337.
Jemal, A., Center, M.M., Desantis, C., et al., 2010. Global patterns of cancer incidence and mortality rates and trends. Cancer Epidemiol. Biomark. Prev. 19, 1893–1907.
Jordan, V.C., 2007. Chemoprevention of breast cancer with selective estrogen- receptor modulators. NatRevCancer 7, 46–53.
Kaneko, E., Matsuda, M., Yamada, Y., et al., 2003. Induction of intestinal ATP-binding cassette transporters by a phytosterol-derived liver X receptor agonist. J. Biol. Chem. 278, 36091–36098.
Kang, R., LouX, T., Tang, D., et al., 2012. The expression of the receptor for advanced glycation endproducts (RAGE) is permissive for early pancreatic neoplasia. Proc.
Khamzina, L., VeilleuX, A., Bergeron, S., Marette, A., 2005. Increased activation of the mammalian target of rapamycin pathway in liver and skeletal muscle of obese rats: possible involvement in obesity-linked insulin resistance. Endocrinology 146, 1473–1481.
Kim, Y.S., Tsao, D., Siddiqui, B., et al., 1980. Effects of sodium butyrate and dimethylsulfoXide on biochemical properties of human colon cancer cells. Cancer 45, 1185–1192.
Kolfschoten, I.G., van Leeuwen, B., Berns, K., et al., 2005. A genetic screen identifies PITX1 as a suppressor of RAS activity and tumorigenicity. Cell 121, 849–858.
Komarova, E.A., Antoch, M.P., Novototskaya, L.R., et al., 2012. Rapamycin extends lifespan and delays tumorigenesis in heterozygous p53 /- mice. Aging 4, 709–714.
Konstantinopoulos, P.A., Vandoros, G.P., Sotiropoulou-Bonikou, G., et al., 2007. NF- kappaB/PPAR gamma and/or AP-1/PPAR gamma “on/off” switches and induction of CBP in colon adenocarcinomas: correlation with COX-2 expression. Int. J. Colorectal Dis. 22, 57–68.
Krishnan, N., Koveal, D., Miller, D.H., et al., 2014. Targeting the disordered C terminus of PTP1B with an allosteric inhibitor. Nat. Chem. Biol. 10, 558–566.
Kuo, M.H., Allis, C.D., 1998. Roles of histone acetyl transferases and deacetylases in gene regulation. Bioessays 20, 615–626.
Larsson, S.C., Orsini, N., Wolk, A., 2005. Diabetes mellitus and risk of colorectal cancer: a meta-analysis. J. Natl. Cancer Inst. 97, 1679–1687.
Lee, J., Park, D., Lee, Y., 2017. Metformin synergistically potentiates the antitumor effects of imatinib in colorectal cancer cells. DevReprod 21, 139–150.
Legeay, S., Fautrat, P., Norman, J.B., Antonova, G., et al., 2020. Selective deficiency in endothelial PTP1B protects from diabetes and endoplasmic reticulum stress- associated endothelial dysfunction via preventing endothelial cell apoptosis. Biomed. Pharmacother. 127, 110200.
Lehmann, J.M., Moore, L.B., Smith-Oliver, T.A., et al., 1995. An antidiabetic thiazolidinedione is a high affinity ligand for PeroXisome Proliferator-Activated Receptor γ (PPARγ). J. Biol. Chem. 270, 12953–12956.
Liao, T.T., Zhao, L.B., Liu, H., He, R.L., et al., 2019. Liraglutide protects from renal damage via Akt-mTOR pathway in rats with diabetic kidney disease. Eur. Rev. Med. Pharmacol. Sci. 23 (3 Suppl), 117–125.
Lo Sasso, G.L., Bovenga, F., Murzilli, S., et al., 2013. Liver X receptors inhibit proliferation of human colorectal cancer cells and growth of intestinal tumors in mice. Gastroenterology 144, 1497–1507.
Lopez Rodas, G., Brosch, G., Georgieva, E.I., et al., 1993. Histone deacetylase. A key enzyme for the binding of regulatory proteins to chromatin. FEBS Lett. 317, 175–180.
Major, J.M., Laughlin, G.A., Kritz-Silverstein, D., et al., 2010. Insulin-like growth factor-I and cancer mortality in older men. J ClinEndocrinolMetab 95, 1054–1059.
Malumbres, M., Barbacid, M., 2009. Cell cycle, CDKs and cancer: a changing paradigm. Nat. Rev. Canc. 9, 153–166.
Mansen, A., Guardiola-Diaz, H., Rafter, J., et al., 1996. EXpression of the peroXisome proliferator-activated receptor (PPAR) in the mouse colonic mucosa. Biochem. Biophys. Res. Commun. 222, 844–851.
Mariadason, J.M., 2008. HDACs and HDAC inhibitors in colon cancer. Epigenetics: official journal of the DNA Methylation Society 3, 28–37.
Mariadason, J.M., Corner, G.A., Augenlicht, L.H., 2000. Genetic reprogramming in pathways of colonic cell maturation induced by short chain fatty acids: comparison with trichostatin A, sulindac and curcumin and implications for chemoprevention of colon cancer. Can. Res. 60, 4561–4572.
Marks, P.A., Dokmanovic, M., 2005. Histone deacetylase inhibitors: discovery and development as anticancer agents. EXpet Opin. Invest. Drugs 14 (12), 1497–1511.
McIntosh, C., Demuth, H., Pospisilik, J., Pederson, R., 2005. Dipeptidyl peptidase IV inhibitors: how do they work as new antidiabetic agents? Regul. Pept. 128, 159–165.
Mehta, A., Patel, B.M., 2019. Therapeutic opportunities in colon cancer: focus on phosphodiesterase inhibitors. Life Sci. 230, 150–161. August.
Meng, F., Song, L., Wang, W., 2017. Metformin improves overall survival of colorectal cancer patients with diabetes: a meta-analysis. J Diabetes Res 5063239, 8, 2017.
Oh, S.W., Kim, Y.H., Choi, Y.S., et al., 2008. The comparison of the risk factors and clinical manifestations of proXimal and distal colorectal cancer. Dis. Colon Rectum 51, 56–61.
Osawa, E., Nakajima, A., Wada, K., et al., 2003. PeroXisome proliferator activated receptor gamma ligands suppress colon carcinogenesis induced by azoXymethanein mice. Gastroenterology 124, 361–367.
Patel, B.M., 2018. Sodium butyrate controls cardiac hypertrophy in experimental models of rats. Cardiovasc. ToXicol. 18 (1), 1–8.
Patel, M., Patel, B.M., 2018. Repurposing of sodium valproate in colon cancer associated with diabetes mellitus: role of HDAC inhibition. Eur. J. Pharmaceut. Sci. 121, 188–199.
Patel, B.M., Shah, N.R., 2016. Secoisolariciresinoldiglucoside rich extract of L. usitatissimum prevents diabetic colon cancer through inhibition of CDK4. Biomed. Pharmacother. 83, 733–739.
Patel, B.M., Raghunathan, S., Porwal, U., 2014. Cardioprotective effects of magnesium valproate in type 2 diabetes mellitus. Eur. J. Pharmacol. 728, 128–134.
Paul, S., Lombroso, P.J., 2003. Receptor and nonreceptor protein tyrosine phosphatases in the nervous system. Cell. Mol. Life Sci. 60, 2465–2482.
Queting, Chen, Yong, Li, Zhong, Li, Qun Zhao, L.F., 2014. Overexpression of PTP1B in human colorectal cancer and its association with tumor progression and prognosis. J. Mol. Histol. 45, 153–159.
Rabadiya, S., Bhadada, S., Dudhrejiya, A., et al., 2018. Magnesium valproate ameliorates type 1 diabetes and cardiomyopathy in diabetic rats through estrogen receptors. Biomed. Pharmacother. 97, 919–927.
Raghunathan, S., Goyal, R.K., Patel, B.M., 2017. Selective inhibition of HDAC2 by magnesium valproate attenuates cardiac hypertrophy. Can. J. Physiol. Pharmacol. 95, 260–267.
Robbins, C.M., 2011. Copy number and targeted mutational analysis reveals novel somatic events in metastatic prostate tumors. Genome Res. 21, 47–55.
Sacaan, A., Thibault, S., Hong, M., et al., 2017. CDK4/6 inhibition on glucose and pancreatic beta cell homeostasis in young and aged rats. Mol. Canc. Res. 15, 1531–1541.
Saha, A.K., Xu, X.J., Balon, T.W., et al., 2011. Insulin resistance due to nutrient excess: is it a consequence of AMPK downregulation? Cell Cycle 10, 3447–3451.
Sakai, K., Dercole, A.J., Murphy, L.J., Clemmons, D.R., 2001. Physiological differences in insulin-like growth factor binding protein-1 (IGFBP-1) phosphorylation in IGFBP-1 transgenic mice. Diabetes 50, 32–38.
Samuels, Y., Wang, Z., Bardelli, A., et al., 2004. High frequency of mutations of the PIK3CA gene in human cancers. Science 304, 554.
Sandhu, M.S., Dunger, D.B., Giovannuci, E.L., 2002. Insulin, insulin-like growth factor-I (IGF-I), IGF binding proteins, their biologic interactions, and colorectal cancer. J. Natl. Cancer Inst. 94, 972–980.
Schoonjans, K., Martin, G., Staels, B., Auwerx, J., 1997. PeroXisome proliferator-activated receptors, orphans with ligands and functions. Curr. Opin. Lipidol. 8, 159–166.
Schultz, J.R., Tu, H., Luk, A., et al., 2000. Role of LXRs in control of lipogenesis. Genes Dev. 14, 2831–2838.
Sealy, L., Chalkley, R., 1978. The effect of sodium butyrate on histone modification. Cell 14, 115–121.
Sekharam, M., Zhao, H., Sun, M., et al., 2003. Insulin-like growth factor 1 receptor enhances invasion and induces resistance to apoptosis of colon cancer cells through the Akt/Bcl-X(L) pathway. Can. Res. 63, 7708–7716.
Shah, O.J., Wang, Z., Hunter, T., 2004. Inappropriate activation of the TSC/Rheb/ mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies. Curr. Biol. 14, 1650–1656.
Shapiro, G.I., 2006. Cyclin-dependent kinase pathways as targets for cancer treatment. J. Clin. Oncol. 24, 1770–1783.
Soung, Y.H., Lee, J.W., Nam, S.W., et al., 2006. Mutational analysis of AKT1, AKT2 and AKT3 genes in common human carcinomas. Oncology 70, 285–289.
Sridhar, S.S., Goodwin, P.J., 2009. Insulin-insulin-like growth factor axis and colon cancer. J. Clin. Oncol. 27, 165–167.
Syed, V., Ulinski, G., Mok, S.C., Yiu, G.K., 2001. EXpression of gonadotropin receptor and growth responses to key reproductive hormones in normal and malignant human ovarian surface epithelial cells. CancerRes 61, 6768–6776.
Takahashi, M., Minamoto, T., Yamashita, N., et al., 1994. Effect of docosahexaenoic acid on azoXymethane-induced colon carcinogenesis in rats. Canc. Lett. 83, 177–184.
Theocharis, S., Giaginis, C., Parasi, A., et al., 2007. EXpression of peroxisome proliferator-activated receptor-gamma in colon cancer: correlation with histopathological parameters, cell cycle-related molecules, and patients’ survival. Dig. Dis. Sci. 52, 2305–2311.
Thomas, C., Gustakfsson, J.Å., 2011. The different roles of ER subtype in cancer biology and therapy. Nat. Rev. Canc. 11, 597–608.
Thompson, E.A., 2007. PPARgamma physiology and pathology in gastrointestinal epithelial cells. Mol. Cell. 24, 167–176.
Tonks, N.K., 2006. Protein tyrosine phosphatases: from genes, to function, to disease. Nat. Rev. Mol. Cell Biol. 11, 833–846.
Tontonoz, P., Mangelsdorf, D.J., 2003. Liver X receptor signaling pathways in cardiovascular disease. Mol. Endocrinol. 17, 985–993.
Tontonoz, P., Hu, E., Spiegelman, B.M., 1994. Stimulation of adipogenesis in fibroblasts by PPARγ2, a lipid-activated transcription factor. Cell 79, 1147–1156.
Tontonoz, P., Singer, S., Forman, B.M., et al., 1997. Terminal differentiation of human liposarcoma cells induced by ligands for peroXisome proliferator-activated receptor gamma and the retinoid X receptor. ProcNatlAcadSci U S 94, 237–241.
Toogood, P.L., Harvey, P.J., Repine, J.T., et al., 2005. Discovery of a potent and selective inhibitor of cyclin dependent kinase 4/6. J. Med. Chem. 48, 2388–2406.
Tran, T.T., Medline, A., Bruce, W.R., 1996. Insulin promotion of colon tumors in rats. Cancer Epidemiol. Biomark. Prev. 5, 1013–1015.
Tremblay, F., Krebs, M., Dombrowski, L., et al., 2005. Overactivation of S6 kinase 1 as a cause of human insulin resistance during increased amino acid availability. Diabetes 54, 2674–2684.
Tremblay, F., Brûle, S., Hee Um, S., et al., 2007. Identification of IRS-1 Ser-1101 as a target of S6K1 in nutrient- and obesity-induced insulin resistance. ProcNatlAcadSci USA 104, 14056–14061.
Tzatsos, A., Kandror, K.V., 2006. Nutrients suppress phosphatidylinositol 3-kinase/Akt signaling via raptor-dependent mTOR-mediated insulin receptor substrate 1 phosphorylation. Mol. Cell Biol. 26, 63–76.
Uno, S., Endo, K., Jeong, Y., et al., 2009. Suppression of beta-catenin signaling by liver X receptor ligands. Biochem. Pharmacol. 77, 186–195.
Vedin, L.L., Lewandowski, S.A., Parini, P., et al., 2009. The oXysterol receptor LXR inhibits proliferation of human breast cancer cells. Carcinogenesis 30, 575–579.
Vermeulen, K., Van Bockstaele, D.R., Berneman, Z.N., 2003. The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer. Cell Prolif 36, 131–149.
Wang, P., Liu, Q., Lee, S., 2019. Diabetes associated oXidative damage to DNA base in colon cells. ActaBiochimBiophys Sin (Shanghai). 23 (5), 542–544, 51.
Wang, Z., Li, J., Wang, Y., Liu, Q., 2019. Palbociclib improves cardiac dysfunction in diabetic cardiomyopathy by regulating Rbphosphorylation. Am J Transl Res 15 (6), 3481–3489, 11.
Warburg, O., 1956. On the origin of cancer cells. Science 123 (3191), 309–314.
Wei, Q., Zhang, B., Li, P., Wen, X., et al., 2019. Maslinic acid inhibits colon tumorigenesis by the AMPK-mTOR signaling pathway. J. Agric. Food Chem. 17 (15), 4259–4272, 67.
Wilson, P.M., et al., 2010. A phase I/II trial of vorinostat in combination with 5-fluoro- uracil in patients with metastatic colorectal cancer who previously failed 5-FU-based chemotherapy. Canc. Chemother. Pharmacol. 979–988.
Wu, Y., Yakar, S., Zhao, L., et al., 2002. Circulating insulin-like growth factor-I levels regulate colon cancer growth and metastasis. Can. Res. 62, 1030–1035.
Wu, Y., Cui, K., Miyoshi, K., et al., 2003. Reduced circulating insulin-like growth factor I levels delay the onset of chemically and genetically induced mammary tumors. Can. Res. 63, 4384–4388.
Yang, Y.X., Hennessy, S., Lewis, J.D., 2004. Insulin therapy and colorectal cancer risk among type 2 diabetes mellitus patients. Gastroenterology 127, 1044–1050.
Yang, Y.X., Hennessy, S., Lewis, J.D., 2005. Type 2 diabetes mellitus and the risk of colorectal cancer. Clin. Gastroenterol. Hepatol. 3, 587–594.
Yun, J., Rago, C., Cheong, I., et al., 2009. Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells. Science 325 (5947), 1555–1559.
Zhang, Y.J., Dai, Q., Sun, D.F., et al., 2009. mTOR signaling pathway is a target for the treatment of colorectal cancer. Ann. Surg Oncol. 16, 2617–2628.
Zhang, Y., Kurup, P., Xu, J., et al., 2010. Genetic reduction of striatal-enriched tyrosine phosphatase (STEP) reverses cognitive and cellular deficits in an Alzheimer’s disease mouse model. Proc. Natl. Acad. Sci. U.S.A. 107, 19014–19019.
Zhou, X.P., Loukola, A., Salovaara, R., et al., 2002. PTEN mutational spectra, expression levels, and subcellular localization in microsatellite stable and unstable colorectal cancers. Am. J. Pathol. 161, 439–447.
Zhu, S., Bjorge, J.D., Fujita, D.J., 2007. PTP1B contributes to the oncogenic properties of colon cancer cells through Src activation. Can. Res. 67, 10129–10137.