Energy sensing pathways: Bridging type 2 diabetes and colorectal cancer?

Abstract

The recently rapid increase of obesity and type 2 diabetes mellitus has caused great burden to our society. A positive association between type 2 diabetes and risk of colorectal cancer has been reported by increasing epidemiological studies. The molecular mechanism of this connection remains elusive. However, type 2 diabetes may result in abnormal carbohydrate and lipid metabolism, high levels of circulating insulin, insulin growth factor-1, and adipocytokines, as well as chronic inflammation. All these factors could lead to the alteration of energy sensing pathways such as the AMP activated kinase (PRKA), mechanistic (mammalian) target of rapamycin (mTOR), SIRT1, and autophagy signaling pathways. The resulted impaired SIRT1 and autophagy signaling pathway could increase the risk of gene mutation and cancer genesis by decreasing genetic stability and DNA mismatch repair. The dysregulated mTOR and PRKA pathway could remodel cell metabolism during the growth and metastasis of cancer in order for the cancer cell to survive the unfavorable microenvironment such as hypoxia and low blood supply. Moreover, these pathways may be coupling metabolic and epigenetic alterations that are central to oncogenic transformation. Further researches including molecular pathologic epidemiologic studies are warranted to better address the precise links between these two important diseases.

Keywords: Biomarker; Carcinoma; Colon; Energy balance; Molecular pathologic epidemiology; PRKA.

Figure 1

Roles of AMPK in cancer in type 2 diabetes. Under nutrition deficiency state, such as fasting, exercise, glucose deprivation, increased AMP activates AMPK which then switches off the synthesis of protein, fatty acid and cholesterol, but switches on the glycolysis and autophagy in order for the cell to survive in energy insufficient. However, in type 2 diabetes, AMPK is inhibited by high levels of plasma glucose, insulin and IGF1, which may promote anabolism to meet the increasing demanding of cancer cell growth. CaMMKK:calmodulin-dependent protein kinase 1 alpha; AICAR: 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide; GLUT4: Glucose transporter 4; PFK-2: phosphofructokinase-2; eEF-2: eukaryotic translation elongation factor 2; STK11 (LKB1: Liver kinase B1); AMPK: AMP-activated protein kinase; ACC: acetyl-CoA carboxylase; IGF1: insulin growth factor-1; PI3K: phosphatidylinositol 3-kinase; PDPK1: phosphoinositide-dependent kinase-1; AKT: proteinase kinase B; mTOR: mechanistic (mammalian) target of rapamycin; ULK: Unc-51-Like Kinases; HMG-CoA:3-hydroxy-3-methylglutaryl-coenzyme A

Figure 2

Roles of mTOR signaling pathway in cancer in type 2 diabetes. mTOR signaling pathway is a key energy sensing pathway. In type 2 diabetes, the high level of nutrition (glucose, FFA and amino acid) as well as increased level of ROS, adipokines, insulin and IGF1, all contribute to the activation of mTOR. The activated mTOR will then inhibit autophagy, promote the synthesis of protein and fatty acid, up-regulate glycolysis, and stimulate angiogenesis, which is helpful for the cancer cell growth and metastasis. GLUT1: Glucose transporter 1; PRKA: AMPK, AMP-activated protein kinase; IGF1: insulin growth factor-1; PI3K: Phosphatidylinositol 3-kinase; PDPK1: phosphoinositide-dependent kinase-1; AKT: proteinase kinase B; mTOR: mammalian target of rapamycin; ULK: Unc-51-Like kinases; IKBKB: IKKkappa, I kappa B kinase; ROS: Reactive oxygen species; HIF1A: HIF-1alpha, Hypoxia-inducible factor-1 alpha; VEGFA: VEGF, Vascular endothelial growth factor; LDH: Lactate dehydrogenase; SREBF: SREBP, sterol regulatory element-binding proteins; FASN: Fatty acid synthase.

Figure 3

Roles of SIRT1 signaling pathway in cancer in type 2 diabetes. SIRT1 signaling pathway is an important energy sensing pathway bridging energy metabolism to DNA stability. In type 2 diabetes, the high level of glucose and FFA will reduce the level of NAD+/NADH, which then decrease SIRT1 activity. The decreased SIRT1 activity loses its stimulation of fatty acid metabolism and its ability to maintain genomic stability, as well as its inhibition of inflammation and angiogenesis. All of those alterations may initiate the formation and growth of cancer cell. FFA: free fatty acid; PRKA: AMPK, AMP-activated protein kinase; mTOR: mammalian target of rapamycin; HIF1A: Hypoxia-inducible factor; VEGFA: VEGF, Vascular endothelial growth factor; NAD: Nicotinamide adenine dinucleotide; SIRT1: NAD-dependent deacetylase sirtuin-1; STK11: LKB1, liver kinase B1; PPARGC1A: PCG-1alpha, peroxisome proliferator-activated receptor gamma coactivator-1 α; LXR: liver X receptor; NFKB1: NF-kappaB, Nuclear factor-KappaB; HDAC1: histone deacetylase 1

Figure 4

Roles of Autophagy signaling pathway in cancer in type 2 diabetes. Autophagy has been found to limit inflammation, mitochondrial dysfunction and genome instability which are known promoters of cancer initiation. In type 2 diabetes, the high level of nutrition (glucose, FFA and amino acid) as well as increased level of ROS, insulin and IGF1, all contribute to the inhibition of autophagy, which may play key role in the initiation of cancer of type 2 diabetes. PRKA: AMP-activated protein kinase; IGF1: insulin growth factor-1; PI3K: Phosphatidylinositol 3-kinase; PDPK1: phosphoinositide-dependent kinase-1; AKT: proteinase kinase B; mTOR: mammalian target of rapamycin; ULK: Unc-51-Like kinases; IKBKB: I kappa B kinase; ROS: Reactive oxygen species; HIF1A: Hypoxia-inducible factor; VEGFA: VEGF, Vascular endothelial growth factor; LDH: Lactate dehydrogenase; SREBF: Sterol regulatory element-binding proteins; FASN: Fatty acid synthase; TSC: Tuberous sclerosis complex; BECN1: Beclin 1

Figure 5

Alteration and interaction of energy sensing pathways in type 2 diabetes and their association with colorectal cancer. The energy sensing pathways are dysregulated in type 2 diabetes because of high glucose, insulin and IGF-1 level. In the mean time, these dysregulated pathways may then increase the risk of carcinogenesis by decreasing genetic stability and DNA mismatch repair to promote cancer genesis, or remodeling cell metabolism to promote protein synthesis, nucleotide synthesis and lipids synthesis which will favor the rapid proliferation of cancer cell. AMPK: AMP-activated protein kinase; IGF-1: insulin growth factor-1; mTORC1: mammalian target of rapamycin complex 1.