Cancer Biology and Prevention in Diabetes

Abstract

The available evidence suggests a complex relationship between diabetes and cancer. Epidemiological data suggest a positive correlation, however, in certain types of cancer, a more complex picture emerges, such as in some site-specific cancers being specific to type I diabetes but not to type II diabetes. Reports share common and differential mechanisms which affect the relationship between diabetes and cancer. We discuss the use of antidiabetic drugs in a wide range of cancer therapy and cancer therapeutics in the development of hyperglycemia, especially antineoplastic drugs which often induce hyperglycemia by targeting insulin/IGF-1 signaling. Similarly, dipeptidyl peptidase 4 (DPP-4), a well-known target in type II diabetes mellitus, has differential effects on cancer types. Past studies suggest a protective role of DPP-4 inhibitors, but recent studies show that DPP-4 inhibition induces cancer metastasis. Moreover, molecular pathological mechanisms of cancer in diabetes are currently largely unclear. The cancer-causing mechanisms in diabetes have been shown to be complex, including excessive ROS-formation, destruction of essential biomolecules, chronic inflammation, and impaired healing phenomena, collectively leading to carcinogenesis in diabetic conditions. Diabetes-associated epithelial-to-mesenchymal transition (EMT) and endothelial-to-mesenchymal transition (EndMT) contribute to cancer-associated fibroblast (CAF) formation in tumors, allowing the epithelium and endothelium to enable tumor cell extravasation. In this review, we discuss the risk of cancer associated with anti-diabetic therapies, including DPP-4 inhibitors and SGLT2 inhibitors, and the role of catechol-o-methyltransferase (COMT), AMPK, and cell-specific glucocorticoid receptors in cancer biology. We explore possible mechanistic links between diabetes and cancer biology and discuss new therapeutic approaches.

Keywords: AMPK activators; PPPM; antineoplastic therapy and diabetes; catechol-o-methyl-transferase; dipeptidyl peptidase 4; endothelial-cell glucocorticoid receptor; endothelial-to-mesenchymal transition; epithelial-to-mesenchymal transition; incretins; insulin; metformin; multiomics; sodium-glucose cotransporter 2; thiazolidinediones; type I diabetes mellitus and cancer and type II diabetes mellitus and cancer.

Figure 1

Role of DPP4 in cancer biology. In normal diabetic epithelial cells, DPP4 is highly expressed and is associated with lower levels of the CXCL12/CXCR4/mTOR/EMT axis. Inhibition of DPP4 induces TGF-β- independent activation of CXCL12/CXCR4/mTOR/EMT axis, promotes the formation of cancer-associated fibroblasts and accelerates cancer metastasis.

Figure 2

Pathological significance of urinary glucose in the disruption of glucose metabolism. SGLT-2 is highly expressed in diabetic epithelial cells. The function of SGLT-2 is to absorb urinary glucose which can then be reabsorbed into the blood, however, in severe diabetes, this excess glucose accumulates in the cytosol, activates SIRT3-deficiency-associated induction of augmented glycolysis and suppresses fatty acid metabolism. Accumulation of PKM2, HIF1α, and STAT3 phosphorylation play a key role in the disruption of central metabolism, a phenotype that is similar to the Warburg effect in tumor cells. This disruption in central metabolism leads to epithelial cell injury and promotes EMT processes. SGLT-2 inhibition abolishes these effects.

Figure 3

Significance of COMT in regulating metabolic homeostasis. Catechol-o-methyltransferase (COMT) is an enzyme that transmethylates hydroxyestradiol into 2-methoxyestradiol (2-ME). 2-ME is protective in maintaining placental homeostasis and metabolic homeostasis through insulin release from pancreatic β-cells. COMT/2-ME phosphorylates liver AMPK which is linked to glucose homeostasis. COMT/2ME is suppressed in the diabetic liver and is linked to a disruption in glucose homeostasis. In pancreatic β-cells, COMT/2ME is an essential protein for PDX1 phosphorylation and is associated with insulin release. In diabetic conditions, low levels of COMT/2ME repress PDX1 phosphorylation and induce MST1. Activated MST1 leads to β-cell death and is responsible for a reduction in insulin release. Cumulatively, COMT is an essential protein that regulates metabolic insults. Deficiency of COMT results in low levels of 2-ME and the accumulation of 4-hydroxyoestradiol (4-OH-E1 and 4-OH-E2). 4-OH-E1 and 4-OH-E2 are believed to possess malignant properties in several organs.

Figure 4

Functional significance of glucocorticoid receptor in endothelial cells. (A). In normal endothelial cells, in the presence of GCs, GR binds to GREs and activates the transcription and trans-repression of genes responsible for canonical Wnt signaling. Suppressed Wnt/TGF-β signaling leads to lipid homeostasis and low levels of EndMT, therefore contributing to endothelial cell homeostasis. In diabetic endothelial cells, GR level is suppressed, leading to transcriptional activation of genes in the canonical Wnt signaling pathway. Higher levels of Wnt-dependent TGF-β signaling lead to disruption in lipid homeostasis and higher levels of EndMT, thereby disrupting endothelial cell homeostasis. (B). Flowchart showing the role of endothelial cell GR in organ protection.