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MYC activity mitigates response to rapamycin in prostate cancer through eukaryotic initiation factor 4E-binding

Bala S Balakumaran1, Alessandro Porrello, David S Hsu

  • 1Duke Institute for Genome Sciences and Policy and Duke Comprehensive Cancer Center, Duke University, NC 27710, USA.

Cancer Research
|September 24, 2009
PubMed

Insights

MYC overexpression in prostate cancer reduces sensitivity to mTOR inhibitors like rapamycin by increasing 4EBP1 expression, hindering cell death and autophagy. Restoring 4EBP1 levels resensitizes cells to rapamycin treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Advanced prostate cancer often involves PTEN loss and PI3K pathway activation.
  • Mammalian target of rapamycin (mTOR) inhibition shows promise but faces limited clinical efficacy.
  • Understanding resistance mechanisms to mTOR inhibitors is crucial for effective prostate cancer treatment.

Purpose of the Study:

  • To investigate how MYC, a gene amplified in prostate cancer, affects sensitivity to mTOR inhibition.
  • To identify molecular mediators of MYC-driven resistance to rapamycin.
  • To explore therapeutic strategies for overcoming MYC-mediated resistance.

Main Methods:

  • Utilized genetically engineered human prostate epithelial cells (PrEC) with MYC manipulation.
  • Analyzed MYC and mTOR pathway components in prostate tumors and cell lines.
  • Assessed rapamycin-induced cytostasis, apoptosis, and autophagy.
  • Investigated the binding of MYC to the 4EBP1 gene promoter.
  • Examined the effect of 4EBP1 suppression on rapamycin sensitivity.

Main Results:

  • MYC expression abrogates sensitivity to rapamycin, reducing cytostasis and autophagy.
  • Increased MYC levels correlate with elevated eukaryotic initiation factor 4E-binding protein 1 (4EBP1) expression.
  • MYC directly binds to regulatory regions of the 4EBP1 gene.
  • Suppression of 4EBP1 restores rapamycin sensitivity and enhances autophagy in MYC-expressing cells.

Conclusions:

  • MYC confers resistance to rapamycin in prostate cancer by upregulating 4EBP1.
  • This MYC-driven 4EBP1 upregulation inhibits autophagy and reduces therapeutic efficacy.
  • Targeting the MYC-4EBP1 axis may overcome resistance to mTOR inhibitors in prostate cancer.

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