Rictor Loss Prevents Ovarian Cancer Development Induced By Kras Activation And Pten Loss In Mice

Abnormality of the PI3K/AKT/mTOR signaling pathway occurs in nearly 70% of ovarian cancer cases.mTOR performs its functions by constituting two different complexes: mTORC1-Raptor and mTORC2-Rictor.mTORC1 responds to nutrients and is closely related to protein synthesis.mTORC2 is sensitive to extracellular growth factors and plays an important role in cytoskeletal reorganization,proliferation and survival.As a scaffold protein,Rictor can regulate the assembly,localization and substrate binding of mTORC2.Rictor/mTORC2 can directly activate Insulin/PI3K/AKT signaling pathway,which plays an important role in cell metabolism,growth and differentiation,immune function regulation.In the present study,we demonstrated that deletion of Rictor gene significantly inhibits the development of ovarian endometrioid adenocarcinoma in mice driven by Kras activation and Pten loss.In the malignant transformation of normal epithelial cells,Rictor/mTORC2 mediates the upregulation of glutathione metabolism as an intracellular antioxidant program to counteract the oxidative challenges that arise in the process of rapid cell proliferation and metabolism,and provide a reduced environment to promote tumor onset.This reduced environment promotes the synergistic effect of the Kras/Pten mutations in PI3K/AKT/Foxo3 a pathway and Wnt/?-catenin pathway to promote the malignant transformation of normal ovarian surface epithelial cells.Rictor deletion,on the one hand,mediates the closure of PI3K/AKT signaling and promotes the nuclear localization of the transcription factor Foxo3 a.On the other hand,Rictor loss suppresses glutathione metabolism and induces intracellular oxidative stress,which activates Foxo3 a.In the status of oxidative stress,the nuclear-localized Foxo3 a competitively binds to?-catenin,which leads to the decrease of binding of ?-catenin and Tcf4,and inhibits the activation of the classic Wnt/?-catenin signaling pathway.With the simultaneous closure of PI3K/AKT pathway and Wn/?-catenin pathway,malignant transformation of epithelial cells is arrested.Thus,Rictor/m TORC2 promotes ovarian cancer by maintaining redox homeostasis,activating PI3K/AKT pathway and Wnt/?-catenin pathway synchronously.