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

Oncogene volume 44, pages 1820–1832 (2025)Cite this article

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Abstract

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.

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Fig. 1: Rictor/mTORC2 is required for the development of ovarian cancer induced by Kras activation and Pten loss in mice.
Fig. 2: Rictor deletion results in disrupted glutathione metabolism.
Fig. 3: Rictor/mTORC2 signaling regulates glutathione metabolism by modulating Nrf2.
Fig. 4: Rictor loss causes oxidative damage and activates FOXO3a signaling.
Fig. 5: Kras activation and Pten deletion synergistically enhance Wnt/β-cat pathway activation.
Fig. 6: Rictor deletion antagonizes the activity of Wnt/β-cat signaling and decreases tumor development.

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Data availability

The datasets used and/or analyzed in this study are available from the corresponding author upon reasonable request.

References

  1. Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease. Cell. 2017;168:960–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Panwar V, Singh A, Bhatt M, Tonk RK, Azizov S, Raza AS, et al. Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease. Signal Transduct Target Ther. 2023;8:375.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Duvel K, Yecies JL, Menon S, Raman P, Lipovsky AI, Souza AL, et al. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol Cell. 2010;39:171–83.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Hagiwara A, Cornu M, Cybulski N, Polak P, Betz C, Trapani F, et al. Hepatic mTORC2 activates glycolysis and lipogenesis through Akt, glucokinase, and SREBP1c. Cell Metab. 2012;15:725–38.

    Article  CAS  PubMed  Google Scholar 

  5. Kumar A, Harris TE, Keller SR, Choi KM, Magnuson MA, Lawrence JC Jr. Muscle-specific deletion of rictor impairs insulin-stimulated glucose transport and enhances Basal glycogen synthase activity. Mol Cell Biol. 2008;28:61–70.

    Article  CAS  PubMed  Google Scholar 

  6. Kumar A, Lawrence JC Jr., Jung DY, Ko HJ, Keller SR, Kim JK, et al. Fat cell-specific ablation of rictor in mice impairs insulin-regulated fat cell and whole-body glucose and lipid metabolism. Diabetes. 2010;59:1397–406.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Jacinto E, Loewith R, Schmidt A, Lin S, Ruegg MA, Hall A, et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol. 2004;6:1122–8.

    Article  CAS  PubMed  Google Scholar 

  8. Gan X, Wang J, Wang C, Sommer E, Kozasa T, Srinivasula S, et al. PRR5L degradation promotes mTORC2-mediated PKC-delta phosphorylation and cell migration downstream of Galpha12. Nat Cell Biol. 2012;14:686–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Chen Z, Kang X, Wang L, Dong H, Wang C, Xiong Z, et al. Rictor/mTORC2 pathway in oocytes regulates folliculogenesis, and its inactivation causes premature ovarian failure. J Biol Chem. 2015;290:6387–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Gu Y, Lindner J, Kumar A, Yuan W, Magnuson MA. Rictor/mTORC2 is essential for maintaining a balance between beta-cell proliferation and cell size. Diabetes. 2011;60:827–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Morrison MM, Young CD, Wang S, Sobolik T, Sanchez VM, Hicks DJ, et al. mTOR directs breast morphogenesis through the PKC-alpha-Rac1 signaling axis. PLoS Genet. 2015;11:e1005291.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Sklarz T, Guan P, Gohil M, Cotton RM, Ge MQ, Haczku A, et al. mTORC2 regulates multiple aspects of NKT-cell development and function. Eur J Immunol. 2017;47:516–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wang Y, Tian Q, Hao Y, Yao W, Lu J, Chen C, et al. The kinase complex mTORC2 promotes the longevity of virus-specific memory CD4(+) T cells by preventing ferroptosis. Nat Immunol. 2022;23:303–17.

    Article  PubMed  Google Scholar 

  14. Sparks CA, Guertin DA. Targeting mTOR: prospects for mTOR complex 2 inhibitors in cancer therapy. Oncogene. 2010;29:3733–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wang C, Chen Z, Yi Y, Ding Y, Xu F, Kang H, et al. RBM45 reprograms lipid metabolism promoting hepatocellular carcinoma via Rictor and ACSL1/ACSL4. Oncogene. 2024;43:328–40.

    Article  CAS  PubMed  Google Scholar 

  16. Marques-Ramos A, Cervantes R. Expression of mTOR in normal and pathological conditions. Mol Cancer. 2023;22:112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kaibori M, Shikata N, Sakaguchi T, Ishizaki M, Matsui K, Iida H, et al. Influence of rictor and raptor expression of mTOR signaling on long-term outcomes of patients with hepatocellular carcinoma. Dig Dis Sci. 2015;60:919–28.

    Article  CAS  PubMed  Google Scholar 

  18. Masri J, Bernath A, Martin J, Jo OD, Vartanian R, Funk A, et al. mTORC2 activity is elevated in gliomas and promotes growth and cell motility via overexpression of rictor. Cancer Res. 2007;67:11712–20.

    Article  CAS  PubMed  Google Scholar 

  19. Tanaka K, Babic I, Nathanson D, Akhavan D, Guo D, Gini B, et al. Oncogenic EGFR signaling activates an mTORC2-NF-kappaB pathway that promotes chemotherapy resistance. Cancer Discov. 2011;1:524–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Gulhati P, Cai Q, Li J, Liu J, Rychahou PG, Qiu S, et al. Targeted inhibition of mammalian target of rapamycin signaling inhibits tumorigenesis of colorectal cancer. Clin Cancer Res. 2009;15:7207–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wang W, Shen T, Dong B, Creighton CJ, Meng Y, Zhou W, et al. MAPK4 overexpression promotes tumor progression via noncanonical activation of AKT/mTOR signaling. J Clin Investig. 2019;129:1015–29.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Guertin DA, Stevens DM, Saitoh M, Kinkel S, Crosby K, Sheen JH, et al. mTOR complex 2 is required for the development of prostate cancer induced by Pten loss in mice. Cancer Cell. 2009;15:148–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Driscoll DR, Karim SA, Sano M, Gay DM, Jacob W, Yu J, et al. mTORC2 signaling drives the development and progression of pancreatic cancer. Cancer Res. 2016;76:6911–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Guri Y, Colombi M, Dazert E, Hindupur SK, Roszik J, Moes S, et al. mTORC2 promotes tumorigenesis via lipid synthesis. Cancer Cell. 2017;32:807–823.e812.

    Article  CAS  PubMed  Google Scholar 

  25. Zinzalla V, Stracka D, Oppliger W, Hall MN. Activation of mTORC2 by association with the ribosome. Cell. 2011;144:757–68.

    Article  CAS  PubMed  Google Scholar 

  26. Cheng H, Zou Y, Ross JS, Wang K, Liu X, Halmos B, et al. RICTOR amplification defines a novel subset of patients with lung cancer who may benefit from treatment with mTORC1/2 inhibitors. Cancer Discov. 2015;5:1262–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Morrison Joly M, Hicks DJ, Jones B, Sanchez V, Estrada MV, Young C, et al. Rictor/mTORC2 Drives progression and therapeutic resistance of HER2-amplified breast cancers. Cancer Res. 2016;76:4752–64.

    Article  CAS  PubMed  Google Scholar 

  28. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7–30.

    Article  PubMed  Google Scholar 

  29. Vaughan S, Coward JI, Bast RC Jr., Berchuck A, Berek JS, Brenton JD, et al. Rethinking ovarian cancer: recommendations for improving outcomes. Nat Rev Cancer. 2011;11:719–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Qin T, Hu Z, Zhang L, Lu F, Xiao R, Liu Y, et al. Genomic profiling of a multi-lineage and multi-passage patient-derived xenograft biobank reflects heterogeneity of ovarian cancer. Cell Rep Med. 2024;5:101631.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Cancer Genome Atlas Research N. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474:609–15.

    Article  Google Scholar 

  32. Vanderstichele A, Busschaert P, Smeets D, Landolfo C, Van Nieuwenhuysen E, Leunen K, et al. Chromosomal instability in cell-free DNA as a highly specific biomarker for detection of ovarian cancer in women with adnexal masses. Clin Cancer Res. 2017;23:2223–31.

    Article  CAS  PubMed  Google Scholar 

  33. Hanrahan AJ, Schultz N, Westfal ML, Sakr RA, Giri DD, Scarperi S, et al. Genomic complexity and AKT dependence in serous ovarian cancer. Cancer Discov. 2012;2:56–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Tuveson DA, Shaw AT, Willis NA, Silver DP, Jackson EL, Chang S, et al. Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell. 2004;5:375–87.

    Article  CAS  PubMed  Google Scholar 

  35. Lesche R, Groszer M, Gao J, Wang Y, Messing A, Sun H, et al. Cre/loxP-mediated inactivation of the murine Pten tumor suppressor gene. Genesis. 2002;32:148–9.

    Article  CAS  PubMed  Google Scholar 

  36. Zhang Y, Hu T, Hua C, Gu J, Zhang L, Hao S, et al. Rictor is required for early B cell development in bone marrow. PLoS ONE. 2014;9:e103970.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Dinulescu DM, Ince TA, Quade BJ, Shafer SA, Crowley D, Jacks T. Role of K-ras and Pten in the development of mouse models of endometriosis and endometrioid ovarian cancer. Nat Med. 2005;11:63–70.

    Article  CAS  PubMed  Google Scholar 

  38. Lai H, Zhao X, Qin Y, Ding Y, Chen R, Li G, et al. FAK-ERK activation in cell/matrix adhesion induced by the loss of apolipoprotein E stimulates the malignant progression of ovarian cancer. J Exp Clin Cancer Res. 2018;37:32.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Zhai W, Zhu R, Ma J, Gong D, Zhang H, Zhang J, et al. A positive feed-forward loop between LncRNA-URRCC and EGFL7/P-AKT/FOXO3 signaling promotes proliferation and metastasis of clear cell renal cell carcinoma. Mol Cancer. 2019;18:81.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Gopinath S, Alapati K, Malla RR, Gondi CS, Mohanam S, Dinh DH, et al. Mechanism of p27 upregulation induced by downregulation of cathepsin B and uPAR in glioma. Mol Oncol. 2011;5:426–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Pillai R, Hayashi M, Zavitsanou AM, Papagiannakopoulos T. NRF2: KEAPing tumors protected. Cancer Discov. 2022;12:625–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Gorrini C, Harris IS, Mak TW. Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov. 2013;12:931–47.

    Article  CAS  PubMed  Google Scholar 

  43. Essers MA, de Vries-Smits LM, Barker N, Polderman PE, Burgering BM, Korswagen HC. Functional interaction between beta-catenin and FOXO in oxidative stress signaling. Science. 2005;308:1181–4.

    Article  CAS  PubMed  Google Scholar 

  44. Jamieson C, Sharma M, Henderson BR. Targeting the beta-catenin nuclear transport pathway in cancer. Semin Cancer Biol. 2014;27:20–9.

    Article  CAS  PubMed  Google Scholar 

  45. Fang L, Zhu Q, Neuenschwander M, Specker E, Wulf-Goldenberg A, Weis WI, et al. A small-molecule antagonist of the beta-catenin/TCF4 interaction blocks the self-renewal of cancer stem cells and suppresses tumorigenesis. Cancer Res. 2016;76:891–901.

    Article  CAS  PubMed  Google Scholar 

  46. Moloughney JG, Kim PK, Vega-Cotto NM, Wu CC, Zhang S, Adlam M, et al. mTORC2 responds to glutamine catabolite levels to modulate the hexosamine biosynthesis enzyme GFAT1. Mol Cell. 2016;63:811–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Jones KT, Greer ER, Pearce D, Ashrafi K. Rictor/TORC2 regulates Caenorhabditis elegans fat storage, body size, and development through sgk-1. PLoS Biol. 2009;7:e60.

    Article  PubMed  Google Scholar 

  48. Hung CM, Calejman CM, Sanchez-Gurmaches J, Li H, Clish CB, Hettmer S, et al. Rictor/mTORC2 loss in the Myf5 lineage reprograms brown fat metabolism and protects mice against obesity and metabolic disease. Cell Rep. 2014;8:256–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Van de Velde LA, Murray PJ. Proliferating helper T cells require rictor/mTORC2 complex to integrate signals from limiting environmental amino acids. J Biol Chem. 2016;291:25815–22.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Cantor JR, Sabatini DM. Cancer cell metabolism: one hallmark, many faces. Cancer Discov. 2012;2:881–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Harris IS, Treloar AE, Inoue S, Sasaki M, Gorrini C, Lee KC, et al. Glutathione and thioredoxin antioxidant pathways synergize to drive cancer initiation and progression. Cancer Cell. 2015;27:211–22.

    Article  CAS  PubMed  Google Scholar 

  52. Lien EC, Lyssiotis CA, Juvekar A, Hu H, Asara JM, Cantley LC, et al. Glutathione biosynthesis is a metabolic vulnerability in PI(3)K/Akt-driven breast cancer. Nat Cell Biol. 2016;18:572–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Cho KR, Shih IeM. Ovarian cancer. Annu Rev Pathol. 2009;4:287–313.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Wu R, Hendrix-Lucas N, Kuick R, Zhai Y, Schwartz DR, Akyol A, et al. Mouse model of human ovarian endometrioid adenocarcinoma based on somatic defects in the Wnt/beta-catenin and PI3K/Pten signaling pathways. Cancer Cell. 2007;11:321–33.

    Article  CAS  PubMed  Google Scholar 

  55. McCubrey JA, Steelman LS, Bertrand FE, Davis NM, Abrams SL, Montalto G, et al. Multifaceted roles of GSK-3 and Wnt/beta-catenin in hematopoiesis and leukemogenesis: opportunities for therapeutic intervention. Leukemia. 2014;28:15–33.

    Article  CAS  PubMed  Google Scholar 

  56. Conde-Perez A, Gros G, Longvert C, Pedersen M, Petit V, Aktary Z, et al. A caveolin-dependent and PI3K/AKT-independent role of PTEN in beta-catenin transcriptional activity. Nat Commun. 2015;6:8093.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81572565; 81874109; 82272707; 82303038; 82072894; 82303279; 81602291) and China Postdoctoral Science Foundation (2023M731198).

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Author notes

  1. These authors contributed equally: Xuejiao Zhao, Huiling Lai, Guannan Li.

Authors and Affiliations

  1. 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

    Xuejiao Zhao, Guannan Li, Yu Qin, Ruqi Chen, Ding Ma, Qinglei Gao & Yong Fang

  2. Department of Gynaecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Xuejiao Zhao, Guannan Li, Yu Qin, Ruqi Chen, Ding Ma, Qinglei Gao & Yong Fang

  3. Department of Gynecology, the Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China

    Huiling Lai

  4. Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada

    Marilyne Labrie

  5. Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA

    Jayne M. Stommel & Gordon B. Mills

  6. Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, USA

    Gordon B. Mills

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Contributions

XZ, HL, and GL performed the experiments and drafted the manuscript. YQ, RC, ML, JS, and GM analyzed the data and interpreted the results. YF, QG, and DM designed the study and revised the manuscript.

Corresponding authors

Correspondence to Ding Ma, Qinglei Gao or Yong Fang.

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Competing interests

GM is a SAB member/Consultant for Amphista, Astex, AstraZeneca, Biodyne, BlueDot, Chrysallis Biotechnology, Ellipses Pharma, GSK, ImmunoMET, Infinity, Ionis, Leapfrog Bio, Lilly, Medacorp, Nanostring, Neophore, Nerviano, Nuvectis, Pangea, PDX Pharmaceuticals, Qureator, Roche, Rybodyne, Signalchem Lifesciences, Tarveda, Turbine, Zentalis Pharmaceuticals has Stock/Options/Financial contributions from Bluedot, Biodyne, Catena Pharmaceuticals, ImmunoMet, Nuvectis, RyboDyne, SignalChem, Tarveda, Turbine has Licensed Technology HRD assay to Myriad Genetics, DSP patents with Nanostring and has sponsored or collaborative research with AstraZeneca, Zentalis, and Nanostring. G.M. has received support that is not directly related to this manuscript. The authors declare no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Ethics approval and consent to participate

All methods were conducted in strict accordance with relevant guidelines and regulations. Mouse experiments were performed under a protocol approved by the Ethics Committee of Tongji Hospital, Tongji Medical College. Patient samples were sourced from the Clinical Database and Biobank of Patients with Gynecologic Neoplasm, registered under ClinicalTrials.gov Identifier NCT01267851. Ethical approval details can be accessed at https://clinicaltrials.gov/ct2/show/study/NCT01267851.

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Zhao, X., Lai, H., Li, G. et al. Rictor orchestrates β-catenin/FOXO balance by maintaining redox homeostasis during development of ovarian cancer. Oncogene 44, 1820–1832 (2025). https://doi.org/10.1038/s41388-025-03351-x

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