PTEN, Insulin Resistance and Cancer

Abstract

Background: The tumor suppressor PTEN serves as a negative regulator of PI3K/PTEN/Akt signaling pathway that regulates cellular functions such as cell growth, differentiation, proliferation and migration. The PI3K/PTEN/Akt signaling cascades might also have effect on glucose uptake via translocation of GLUT-4. Insulin controls energy storage and the whole body glucose homeostasis. Its binding to insulin receptor on the surface of diverse cells allows glucose entry into cells, and activates a variety of cellular actions. Insulin resistance is a common metabolic feature and established risk factor of many diseases. Its fundamental principle is inability of insulin to exert its normal metabolic effects, and nutrient imbalance and abnormal lipid accumulation in skeletal muscle, liver and adipose tissues.

Methods: We review the literature on the structure and function of PTEN and its involvement in insulin resistance and tumor regulation, and summarized the detailed scientific achievements on this topic.

Results: Suppressing PTEN expression plays a role in pro- or anti-inflammatory state during insulin resistance associated with obesity. Selective disruption of PTEN in pancreatic α-cells demonstrates that a lack of PTEN reduces circulating glucagon levels and protects against hyperglycemia and insulin resistance in high-fat diet-fed mice. Loss-of-function PTEN mutations in adipose tissue results in systemic glucose tolerance and insulin sensitivity improvement because of ascended recruitment of the GLUT-4 towards the membrane. Targeting tissuespecific PTEN deletion improves insulin sensitivity and protects from systemic insulin resistance. PTEN, as an important tumor suppressor gene, is frequently deleted or mutated in a variety of human tumors. Inactivation of PTEN by loss-of-function mutations leads to deregulated hyperproliferation of cells, leading to oncogenic transformation.

Conclusion: Considering PTEN's important role in insulin resistance and tumor regulation, targeting the PTEN gene and/or protein will likely provide an efficient strategy for therapeutic intervention in cancer and metabolic diseases like type 2 diabetes mellitus, obesity, and cardiovascular dysfunction.

Keywords: GLUT-4; PI3K/ Akt signaling; PTEN; cancer; insulin resistance; insulin/IGF system signaling.