Abstract 253: Diet induced insulin resistance is due to induction of expression of tumor suppressor pten

Abstract The PI3K/AKT/mTOR pathway is a key regulator of insulin and metabolic homeostasis, proliferation, growth, and apoptosis. While AKT regulates key processes like glucose uptake, mTOR is a master regulator of cap-dependent translation through its substrates S6K and 4E-BP. This pathway also plays a key role in tumorigenesis- with high incidence of activating mutations in the oncogene PIK3CA and loss of function alterations of tumor suppressor and lipid phosphatase PTEN. Most recently our work led to the discovery that the translation of PTEN lipid phosphatase, is regulated by PI3K-mTOR regulated cap dependent translation, constituting a feedback loop. Pharmacologic inhibition by PI3K inhibitors reduces PTEN protein leading to a rebound in PI3K signaling that reduces the efficacy of the PI3K inhibitors. Insulin resistance is a condition which arises due to inadequate response of the PI3K/AKT signaling to insulin, demanding increasing amount of insulin to elicit the same degree of AKT activation. Onset of insulin resistance is closely associated with a variety metabolic aberrations like type 2 diabetes, obesity and liver steatosis. Insulin resistance and Type 2 Diabetes are characterized by hyperinsulinemia, hyperglycemia with severe cases ending up in insulin deficiency due to pancreatic beta cell exhaustion. There is also a strong association of insulin resistance and increased risk of developing cancer and resistance to cancer therapy especially in breast and endometrial cancers that are mutant for PI3K/PTEN. Currently, little is known about the early kinetics and molecular changes in PI3K/AKT signaling that may allow for the reduced insulin action and therefore progression of insulin resistance. We speculated that insulin resistance is due to insulin dependent induction of its negative regulator PTEN protein that prevent further increases in PI3K signaling. Here we show that in a diet induced model of obesity and insulin resistance, mouse fed on high fat diet, PTEN levels are increased in fat, muscle and liver tissues. Onset of hyperinsulinemia and PTEN induction in tissue is followed by hyperglycemia, hepatic steatosis and severe glucose intolerance. Treatment with a PTEN phosphatase inhibitor prevents and reverses these phenotypes, whereas an mTORC1 kinase inhibitor reverse all but the hepatic steatosis. These data suggest that induction of PTEN by increasing levels of insulin elevates feedback inhibition of the pathway to a point where downstream PI3K signaling is reduced and hyperglycemia ensues. PTEN induction is thus necessary for insulin resistance and the type 2 diabetes phenotype and a potential therapeutic target. This was accompanied by a significant increase in weight, hyperinsulinemia, hyperglycemia, insulin resistance and liver lipidosis. Inhibition of PTEN activity or its translation by inhibiting mTOR, both prevented and reversed the development of insulin resistance and obesity phenotypes Citation Format: Radha Mukherjee, Priya Pancholi, Malvika Sharma, Hilla Solomon, Merna N. Timaul, Vladimir Markov, Elisa de Stanchina de Stanchina, Kiran Vanaja, Neal Rosen. Diet induced insulin resistance is due to induction of expression of tumor suppressor pten [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 253.