A Novel Role of mTORC2 in Diabetes-Associated Colorectal Cancer

Abstract

Background: Type 2 Diabetes mellitus (T2DM) is a chronic systemic dysfunction characterized by persistent metabolic disturbances which result in a high rate of micro and macrovascular events to which cancer was recently annexed. In fact, diabetes increases the risk of colorectal cancer (CRC) by 1.2 to 1.5 folds, leaving patients with increased aggressiveness and poorer 5-year survival. However, the cellular and molecular pathways involved in diabetes-induced CRC progression are not well elucidated. mTORC signaling pathway has been described to play a role in several disease including diabetes or cancer. Yet, the role of the rapamycin insensitive unit, mTORC2, in diabetes-associated cancer is yet to be described. This study aims to identify a potential common mechanistic pathway between diabetes and CRC, especially the one orchestrated by mTORC2. Furthermore, in this study we will evaluate the effect of probiotics treatment on the control and prevention of diabetes-associated CRC. Aims: We hypothesize that the onset of diabetes, cancer or their association induce dysbiosis that stimulates NADPH oxidases-activated ROS production by inducing the mTORC2 signaling pathway alteration. Results: Our data suggest that diabetes and or cancer induce dysbiosis that in turn leads to gastrointestinal complications and induces colorectal cancer aggressiveness. These results are paralleled by an increase in ROS production by activating the NADPH oxidase 4. Of interest, diabetes-associated CRC also exhibits an increase in the mTORC2 signaling pathway. These changes are reversed when treated with probiotics, which corrects the dysbiosis associated with diabetes, cancer, or their association, reduces ROS production, and correct the mTORC2 expression suggesting a beneficial effect on the progression of these chronic comorbidities. Conclusion: Our results clearly support the role of mTORC2 in diabetes associated cancer and advances the protective effect of probiotics treatment in diabetes, cancer, or their association.