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Nelfinavir and bortezomib inhibit mTOR activity via ATF4-mediated sestrin-2 regulation

Ansgar Brüning1, Martina Rahmeh, Klaus Friese

  • 1Department of Obstetrics and Gynecology, Ludwig-Maximilians-University, Munich, Germany.

Molecular Oncology
|August 7, 2013
PubMed

Insights

Endoplasmic reticulum (ER) stress triggers sestrin-2 (SESN2) expression via ATF4, linking ER stress to mTOR inhibition and autophagy. This mechanism explains how nelfinavir induces cancer cell death and radiosensitization.

Area of Science:

  • Cellular Biology
  • Molecular Oncology
  • Cancer Therapeutics

Background:

  • Endoplasmic reticulum (ER) stress and autophagy are critical cell survival pathways.
  • Their interplay in cancer, particularly under chemotherapy, remains incompletely understood.
  • ER stress can induce cancer cell death, but the underlying molecular links require elucidation.

Purpose of the Study:

  • To investigate the molecular link between ER stress and autophagy.
  • To identify key mediators connecting ER stress response to mTOR signaling and autophagy.
  • To explore the role of sestrin-2 (SESN2) in ER stress-induced cellular responses.

Main Methods:

  • Treatment of cancer cells with ER stress-inducing agents (nelfinavir, bortezomib).
  • Analysis of gene expression for ER stress markers (ATF4, ATF3, CHOP) and SESN2.
  • Investigating the role of ATF4 in transcriptional regulation of SESN2.
  • Assessing mTOR activity and autophagy induction upon SESN2 overexpression and nelfinavir treatment.

Main Results:

  • Nelfinavir and bortezomib induced SESN2 expression, correlated with ER stress markers.
  • ATF4, but not ATF3 or CHOP, transcriptionally upregulated SESN2.
  • SESN2 overexpression inhibited mTOR and induced autophagy.
  • Nelfinavir treatment reduced mTOR activity and increased ATF4 and SESN2 levels in cancer cells.

Conclusions:

  • ATF4-mediated SESN2 upregulation establishes a novel link between ER stress and mTOR inhibition.
  • This pathway connects ER stress to autophagy induction, growth arrest, and radiosensitization.
  • Nelfinavir's anticancer effects may be partly explained by its ability to induce ER stress, SESN2, and subsequent autophagy.
Keywords:
AutophagyBortezomibEndoplasmic reticulum stressNelfinavirSESN2mTOR

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