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FBXW7 targets mTOR for degradation and cooperates with PTEN in tumor suppression

Jian-Hua Mao1, Il-Jin Kim, Di Wu

  • 1Cancer Research Institute, University of California at San Francisco, 2340 Sutter Street, San Francisco, CA 94143, USA.

Science (New York, N.Y.)
|September 13, 2008
PubMed

Insights

The tumor suppressor FBXW7 targets the mammalian target of rapamycin (mTOR) for degradation. Loss of FBXW7 in cancer cells indicates sensitivity to mTOR pathway inhibitors like rapamycin.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • The mammalian target of rapamycin (mTOR) pathway is crucial in cell growth and a key target for cancer therapy.
  • Understanding the regulation of mTOR protein levels is vital for developing effective cancer treatments.
  • The role of tumor suppressor proteins in controlling mTOR activity remains largely unexplored.

Purpose of the Study:

  • To elucidate the regulatory mechanisms controlling mammalian target of rapamycin (mTOR) protein levels.
  • To investigate the interaction between FBXW7 and mTOR in the context of cancer.
  • To identify potential biomarkers for predicting response to mTOR-targeted therapies.

Main Methods:

  • Ubiquitination assays to detect mTOR modification.
  • Protein degradation studies to assess mTOR stability.
  • Analysis of human breast cancer cell lines and primary tumors for FBXW7 and PTEN status.
  • Sensitivity assays using rapamycin treatment on tumor cell lines with FBXW7 mutations.

Main Results:

  • The tumor suppressor FBXW7 directly targets mTOR for ubiquitination and subsequent degradation.
  • A reciprocal relationship was observed between FBXW7 loss and PTEN deletion/mutation in human breast cancer.
  • Tumor cell lines with FBXW7 deletions or mutations exhibited heightened sensitivity to rapamycin.

Conclusions:

  • FBXW7 acts as a negative regulator of mTOR protein levels through targeted degradation.
  • Loss of FBXW7, often co-occurring with PTEN alterations, identifies cancers susceptible to mTOR pathway inhibition.
  • FBXW7 status can serve as a predictive biomarker for rapamycin and other mTOR inhibitor therapies in cancer treatment.

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