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Updated: Jun 30, 2026
06:56
Development and Application of Rapamycin-regulated Tyrosine Phosphatases
Published on: September 6, 2024
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.
Summary
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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