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<p>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 <i>Rictor</i> knockout mice, we were able to demonstrate that <i>Rictor</i> deletion disrupted glutathione metabolism through AKT/Nrf2 signaling pathway and induced intracellular oxidative stress during the malignant transformation of <i>Kras</i>/<i>Pten</i>-mutant ovarian surface epithelial cells. Elevated reactive oxygen species and activated FOXO3a in <i>Rictor</i>-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.</p><p></p>

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Rictor orchestrates β-catenin/FOXO balance by maintaining redox homeostasis during development of ovarian cancer

  • 期刊论文

  • 发表日期：

    2025年3月25日

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  • Xuejiao Zhao,
  • Huiling Lai,
  • Guannan Li,
  • Yu Qin,
  • Ruqi Chen,
  • Marilyne Labrie,
  • Jayne M. Stommel,
  • Gordon B. Mills,
  • Ding Ma,
  • Qinglei Gao,
  • Yong Fang

摘要

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.