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CDC25B mediates rapamycin-induced oncogenic responses in cancer cells

Run-Qiang Chen1, Qing-Kai Yang, Bing-Wen Lu

  • 1Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, USA.

Cancer Research
|March 12, 2009
PubMed

Insights

Rapamycin, an mTOR inhibitor, can paradoxically activate oncogenic pathways in cancer. This study identifies CDC25B phosphatase as a key mediator of this effect, suggesting it as a potential therapeutic target to enhance cancer treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • The mammalian target of rapamycin (mTOR) pathway is frequently dysregulated in human cancers.
  • mTOR inhibitors like rapamycin show limited clinical efficacy, potentially due to unclear mechanisms of resistance.
  • Understanding rapamycin's effects on cellular signaling is crucial for improving cancer therapy.

Purpose of the Study:

  • To investigate the phosphoproteomic changes induced by rapamycin.
  • To identify novel regulators of rapamycin-mediated signaling in cancer.
  • To explore CDC25B phosphatase as a potential therapeutic target in combination with mTOR inhibitors.

Main Methods:

  • Phosphoproteomic analysis to identify rapamycin-sensitive phosphosites.
  • siRNA-based screening of regulated kinases and phosphatases.
  • Site-directed mutagenesis to assess the role of CDC25B phosphorylation at Serine375.
  • Evaluation of CDC25B depletion effects on cancer cell lines treated with rapamycin.

Main Results:

  • Rapamycin treatment altered 250 phosphosites in 161 proteins, including kinases and phosphatases.
  • Rapamycin-induced AKT activation was attenuated by depleting CDC25B phosphatase.
  • Phosphorylation of CDC25B at Serine375 is critical for its phosphatase activity and for mediating rapamycin-induced AKT signaling.
  • Depletion of CDC25B enhanced the anticancer effects of rapamycin in various cancer cell lines.

Conclusions:

  • Rapamycin phosphoproteomics reveals CDC25B as a key mediator of rapamycin-induced oncogenic AKT activity.
  • CDC25B phosphorylation at Serine375 is essential for its function in this pathway.
  • Targeting CDC25B may represent a strategy to overcome resistance and improve the efficacy of mTOR-targeted cancer therapies.

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