Prohibitin regulates mTOR pathway via interaction with FKBP8

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Cancer cells exhibit continuous proliferation, driven by oncogene activation and tumor suppressor gene alterations.
• The PI3K-Akt-mTOR signaling pathway is frequently dysregulated in cancer, promoting tumor growth and serving as a key therapeutic target.
• FK506 binding protein 8 (FKBP8) acts as an intrinsic inhibitor of mTOR kinase and possesses anti-apoptotic functions, presenting a complex role in cancer.

Purpose of the Study:

• To elucidate the contradictory roles of FKBP8 in cancer by identifying a regulatory "switch."
• To investigate the interaction between FKBP8 and other cellular proteins, particularly focusing on mitochondrial components.
• To understand how FKBP8's function and localization are modulated in the context of cancer progression.

Main Methods:

• Proteomic analysis using immunoprecipitation-mass spectrometry to identify FKBP8 interacting partners.
• Downregulation of prohibitin 1 (PHB1) in ovarian cancer cells.
• Assessment of ovarian cancer cell proliferation and the PI3K-Akt-mTOR signaling pathway.
• Analysis of FKBP8 localization within mitochondria and its interaction with mTOR.

Main Results:

• Prohibitin 1 (PHB1), a mitochondrial protein, was identified as a specific interactor of FKBP8.
• Downregulation of PHB1 led to decreased ovarian cancer cell proliferation and inhibited the mTOR signaling pathway.
• Reduced PHB1 levels resulted in a significant decrease of FKBP8 within mitochondria.
• The absence of PHB1 increased the interaction between FKBP8 and mTOR.

Conclusions:

• PHB1 acts as a crucial regulator of FKBP8, influencing its subcellular localization and interaction with mTOR.
• The PHB1-FKBP8 interaction is critical for sustaining ovarian cancer cell proliferation and PI3K-Akt-mTOR pathway activity.
• Targeting the PHB1-FKBP8 axis presents a potential therapeutic strategy for ovarian cancer.