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Prohibitin regulates mTOR pathway via interaction with FKBP8

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Abstract

The ability of tumor cells to sustain continuous proliferation is one of the major characteristics of cancer. The activation of oncogenes and the mutation or inactivation of tumor suppressor genes ensure the rapid proliferation of tumor cells. The PI3K-Akt-mTOR axis is one of the most frequently modified signaling pathways whose activation sustains cancer growth. Unsurprisingly, it is also one of the most commonly attempted targets for cancer therapy. FK506 binding protein 8 (FKBP8) is an intrinsic inhibitor of mTOR kinase that also exerts an anti-apoptotic function. We aimed to explain these contradictory aspects of FKBP8 in cancer by identifying a “switch” type regulator. We identified through immunoprecipitation-mass spectrometry-based proteomic analysis that the mitochondrial protein prohibitin 1 (PHB1) specifically interacts with FKBP8. Furthermore, the downregulation of PHB1 inhibited the proliferation of ovarian cancer cells and the mTOR signaling pathway, whereas the FKBP8 level in the mitochondria was substantially reduced. Moreover, concomitant with these changes, the interaction between FKBP8 and mTOR substantially increased in the absence of PHB1. Collectively, our finding highlights PHB1 as a potential regulator of FKBP8 because of its subcellular localization and mTOR regulating role.

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Acknowledgements

This work was funded by Shanghai Pujiang Program (No.18PJ140-6700).

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Authors and Affiliations

  1. Department of Biochemistry and Molecular and Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Jiahui Zhang, Yanan Yin, Jiahui Wang, Wen Yang & Yingjie Xu

  2. Department of Obstetrics and Gynecology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Jingjing Zhang, Hua Liu & Weiwei Feng

  3. Vascular Biology Program, Boston Children’s Hospital, Harvard Medical School, Boston, MA, 02115, USA

    Bruce Zetter

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  1. Jiahui Zhang
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  2. Yanan Yin
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  3. Jiahui Wang
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  5. Hua Liu
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  6. Weiwei Feng
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  7. Wen Yang
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  8. Bruce Zetter
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  9. Yingjie Xu
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Correspondence to Bruce Zetter or Yingjie Xu.

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Compliance with ethics guidelines

Jiahui Zhang, Yanan Yin, Jiahui Wang, Jingjing Zhang, Hua Liu, Weiwei Feng, Wen Yang, Bruce Zetter, and Yingjie Xu declare no conflict of interest. All procedures were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975 as revised in 2000. Additional informed consent was obtained from all patients, whose identifying information is included in this article.

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Zhang, J., Yin, Y., Wang, J. et al. Prohibitin regulates mTOR pathway via interaction with FKBP8. Front. Med. 15, 448–459 (2021). https://doi.org/10.1007/s11684-020-0805-6

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  • DOI: https://doi.org/10.1007/s11684-020-0805-6

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