Zhao Xuejiao, Lai Huiling, Li Guannan, Qin Yu, Chen Ruqi, Labrie Marilyne, Stommel Jayne M, Mills Gordon B, Ma Ding, Gao Qinglei, Fang Yong
National Clinical Research Center for Obstetrics and Gynaecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Gynaecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Oncogene. 2025 Mar 25. doi: 10.1038/s41388-025-03351-x.
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.
Rictor/mTORC2已被证明在多种实体瘤和血液系统恶性肿瘤的发生发展中发挥重要作用。然而，关于Rictor/mTORC2在卵巢癌病理生理学中的作用却知之甚少。在此，我们利用条件性Rictor基因敲除小鼠，证明了Rictor基因缺失通过AKT/Nrf2信号通路破坏了谷胱甘肽代谢，并在Kras/Pten突变的卵巢表面上皮细胞恶性转化过程中诱导了细胞内氧化应激。Rictor基因缺失的细胞中活性氧升高和FOXO3a激活，显著改变了β-连环蛋白从TCF到FOXO3a的功能相互作用，从而强烈抑制经典的Wnt/β-连环蛋白信号通路。我们的研究结果强调了Rictor在卵巢癌发生过程中协调PI3K/AKT和Wnt/β-连环蛋白信号通路串扰方面的关键作用。Rictor/mTORC2通过调节谷胱甘肽代谢和介导致癌信号促进肿瘤发生的示意图。
