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Superoxide anions regulate TORC1 and its ability to bind Fpr1:rapamycin complex

Taavi K Neklesa1, Ronald W Davis

  • 1Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA.

Proceedings of the National Academy of Sciences of the United States of America
|September 25, 2008
PubMed

Insights

Elevated oxidative stress, indicated by increased superoxide anions, causes resistance to the cancer drug rapamycin by preventing its binding to the Target of Rapamycin Complex 1 (TORC1). This finding may explain clinical resistance. Keywords: rapamycin resistance, oxidative stress, TORC1.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cellular Biology

Background:

  • Rapamycin inhibits the Target of Rapamycin Complex 1 (TORC1), crucial for nutrient response, cell growth, and proliferation.
  • Clinical trials using rapamycin as an anticancer agent show limited patient response, necessitating biomarkers for sensitivity or resistance.
  • Understanding mechanisms of rapamycin resistance is vital for improving cancer therapy.

Purpose of the Study:

  • To elucidate the molecular mechanisms of partial rapamycin resistance in yeast.
  • To identify genetic factors contributing to rapamycin resistance.
  • To investigate the role of oxidative stress in rapamycin resistance.

Main Methods:

  • Screening of a yeast deletion collection to identify strains exhibiting partial rapamycin resistance.
  • Analysis of oxidative stress markers, specifically superoxide anion levels.
  • Biochemical assays to assess the binding of the FKBP12:rapamycin complex to TORC1.

Main Results:

  • Fifteen deletion strains conferring partial rapamycin resistance were identified, including those related to oxidative stress (Sod1, Ctr1, Lys7).
  • All identified resistant strains showed elevated levels of superoxide anions.
  • Increased reactive oxygen species were shown to modify TORC1, impairing its binding to the FKBP12:rapamycin complex.

Conclusions:

  • Elevated oxidative stress is a key mechanism underlying partial rapamycin resistance in yeast.
  • Increased reactive oxygen species disrupt the FKBP12:rapamycin-TORC1 interaction, leading to drug resistance.
  • These findings suggest that oxidative stress may also contribute to rapamycin resistance in clinical settings.

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