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Mammalian target of rapamycin regulates murine and human cell differentiation through STAT3/p63/Jagged/Notch cascade

Jianhui Ma1, Yan Meng, David J Kwiatkowski

  • 1Department of Physiology and Pathophysiology, National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China.

The Journal of Clinical Investigation
|December 30, 2009
PubMed

Insights

Activated mTOR signaling promotes cancer by enhancing Notch signaling, impairing cell differentiation. Inhibiting Notch can suppress tumor growth in mTOR-driven cancers, offering a potential therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • The mammalian target of rapamycin (mTOR) pathway is frequently dysregulated in cancer.
  • The precise mechanisms by which activated mTOR drives tumorigenesis, particularly its role in cell differentiation, are not fully understood.

Purpose of the Study:

  • To elucidate the role of mTOR in regulating cancer cell differentiation and tumorigenesis.
  • To investigate the interplay between mTOR and Notch signaling pathways in cancer development.
  • To identify potential therapeutic targets for cancers with hyperactive mTOR signaling.

Main Methods:

  • Utilized mouse and human cell lines, including murine embryonic fibroblasts and breast cancer cells.
  • Investigated the effects of mTOR activation on Notch signaling components (STAT3, p63, Jagged).
  • Analyzed tumor tissues from human lung lymphangioleiomyomatosis (LAM) and mouse kidney tumors.
  • Assessed the impact of Notch inhibition on the tumorigenic potential of cells with hyperactive mTOR.

Main Results:

  • Demonstrated that mTOR positively regulates Notch signaling by inducing the STAT3/p63/Jagged cascade.
  • Showed that mTOR activation impairs cell differentiation via enhanced Notch signaling.
  • Found a strong correlation between elevated mTOR and Notch signaling in poorly differentiated human breast cancers.
  • Observed enhanced STAT3/p63/Notch signaling in tumors with hyperactive mTOR (TSC1/TSC2 deficiency).
  • Confirmed that Notch inhibition suppresses the tumorigenic potential of cells with uncontrolled mTOR signaling.

Conclusions:

  • Aberrant mTOR activation promotes cancer by disrupting cell differentiation through potentiation of Notch signaling.
  • The STAT3/p63/Notch axis is a key mediator of mTOR-driven tumorigenesis and under-differentiation.
  • Targeting the STAT3/p63/Notch axis represents a promising therapeutic strategy for cancers with hyperactive mTOR signaling.

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