Rictor orchestrates β-catenin/FOXO balance by maintaining redox homeostasis during development of ovarian cancer
Rictor/mTORC2 has been demonstrated to have important roles in cancer development and progression in a number of solid and hematologic malignancies. However, little is known about the role of Rictor/mTORC2 in ovarian cancer pathophysiology. Herein, using conditional Rictor knockout mice, we were able to demonstrate that Rictor deletion disrupted glutathione metabolism through AKT/Nrf2 signaling pathway and induced intracellular oxidative stress during the malignant transformation of Kras/Pten-mutant ovarian surface epithelial cells. Elevated reactive oxygen species and activated FOXO3a in Rictor-deleted cells strikingly shifts the functional interaction of β-catenin from TCF to FOXO3a, which strongly inhibits classical Wnt/β-catenin signaling. Our findings emphasize a pivotal role for Rictor in orchestrating crosstalk between the PI3K/AKT and Wnt/β-catenin signaling in the development of ovarian cancer. Illustration of Rictor/mTORC2 in promoting tumor onset by regulating glutathione metabolism and mediating oncogenic signaling.
Journal
OncogeneAuthors
Funding
National Natural Science Foundation of China (National Science Foundation of China) Grant 81572565National Natural Science Foundation of China (National Science Foundation of China) Grant 81874109National Natural Science Foundation of China Grant 82272707National Natural Science Foundation of China (National Science Foundation of China) Grant 82072894National Natural Science Foundation of China (National Science Foundation of China) Grant 81602291National Natural Science Foundation of China (National Science Foundation of China) Grant 82303279National Natural Science Foundation of China (National Science Foundation of China) Grant 82303038National Natural Science Foundation of China Grant 82303279China Postdoctoral Science Foundation Funding