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DNA damage-induced S and G2/M cell cycle arrest requires mTORC2-dependent regulation of Chk1

Jogitha Selvarajah1, Androulla Elia1, Veronica A Carroll1

  • 1Cardiovascular and Cell Sciences Research Institute, St George's University of London, Cranmer Terrace, UK.

Oncotarget
|December 3, 2014
PubMed

Insights

DNA damage activates mTOR signaling, crucial for cancer cell survival. Inhibiting mTOR, particularly mTORC2, combined with chemotherapy, shows promise for treating breast cancer by overcoming treatment resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Signaling

Background:

  • Mammalian target of rapamycin (mTOR) signaling is frequently altered in cancer.
  • mTOR inhibitors show efficacy in certain tumors and are explored in combination therapies.
  • The role of mTORC2 in cancer and DNA damage response is less understood.

Purpose of the Study:

  • To investigate the role of mTOR signaling in the DNA damage response.
  • To determine the specific contributions of mTORC1 and mTORC2 in this process.
  • To evaluate the potential of mTOR inhibitors in overcoming chemotherapy resistance in breast cancer.

Main Methods:

  • DNA damage induction using etoposide.
  • Assessment of mTOR protein levels and kinase activity.
  • Inactivation of mTOR using siRNA and pharmacological inhibitors.
  • Analysis of cell cycle arrest and Chk1 phosphorylation and production.

Main Results:

  • DNA damage transiently increases mTOR protein levels and kinase activity in an ATM/ATR-dependent manner.
  • mTOR inhibition prevents etoposide-induced cell cycle arrest by inhibiting Chk1 phosphorylation and production.
  • mTORC2 is essential, while mTORC1 is dispensable, for this DNA damage response pathway.
  • mTORC1/2 inhibition sensitizes breast cancer cells to chemotherapy.

Conclusions:

  • Breast cancer cells may depend on the mTORC2-Chk1 pathway for survival following DNA damage.
  • mTOR kinase inhibitors could potentially overcome resistance to DNA-damage-based therapies in breast cancer.

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