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Autophagy suppresses RIP kinase-dependent necrosis enabling survival to mTOR inhibition

Kevin Bray1, Robin Mathew, Alexandria Lau

  • 1The Cancer Institute of New Jersey, New Brunswick, New Jersey, United States of America.

Plos One
|August 1, 2012
PubMed

Insights

Autophagy enables renal cancer cells to resist mTOR inhibitors. Blocking both autophagy and mTOR triggers cell death, potentially improving cancer treatment by causing RIPK- and ROS-dependent necroptosis.

Area of Science:

  • Oncology
  • Cell Biology
  • Biochemistry

Background:

  • mTOR inhibitors are used for renal cancer but are not curative.
  • Autophagy is a cellular process that can promote cancer cell survival.
  • Renal cell carcinoma (RCC) exhibits high basal autophagy.

Purpose of the Study:

  • To investigate the role of autophagy as a resistance mechanism to mTOR inhibitors in RCC.
  • To explore the potential of combined mTOR and autophagy inhibition for cancer therapy.

Main Methods:

  • Utilized human RCC cell lines and xenograft models.
  • Administered mTOR inhibitor CCI-779 and autophagy inhibitors.
  • Assessed cell viability, RIP kinase levels, reactive oxygen species (ROS), and necroptosis.

Main Results:

  • RCC cell lines exhibit high basal autophagy crucial for survival under mTOR inhibition.
  • Inhibition of mTOR with CCI-779 stimulates autophagy and decreases RIP kinases.
  • Blocking autophagy alongside mTOR inhibition induces RIPK- and ROS-dependent necroptosis and suppresses tumor growth.
  • Autophagy is essential for mitochondrial survival as mTOR inhibition downregulates Nrf2 antioxidant defense.

Conclusions:

  • Autophagy is a key resistance mechanism in RCC against mTOR inhibitors.
  • Co-inhibition of mTOR and autophagy induces necroptosis, offering a potential strategy to enhance cancer treatment efficacy.
  • Targeting both pathways may overcome resistance and improve outcomes in renal cancer therapy.

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