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Activation of the integrated stress response regulates lovastatin-induced apoptosis

Nima Niknejad1, Melissa Morley, Jim Dimitroulakos

  • 1Centre for Cancer Therapeutics, Ottawa Health Research Institute, Ontario K1H 8L6, Canada.

The Journal of Biological Chemistry
|August 19, 2007
PubMed

Insights

Lovastatin induces apoptosis in head and neck cancer by activating the integrated stress response (ISR) pathway. This involves the transcription factor ATF4 and its downstream targets, independent of proteasome activity.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cellular Stress Response

Background:

  • Lovastatin inhibits mevalonate synthesis and induces apoptosis in certain human tumors, including head and neck squamous cell carcinomas (HNSCC).
  • Activation of transcription factor 4 (ATF4) was identified as a lovastatin-induced gene in HNSCC cells.
  • ATF4 is a key regulator of the integrated stress response (ISR), a cellular mechanism responding to various stress inducers.

Purpose of the Study:

  • To investigate the mechanism by which lovastatin induces apoptosis in HNSCC cells.
  • To determine the role of the integrated stress response (ISR) pathway, specifically ATF4 and its downstream targets, in lovastatin-induced apoptosis.
  • To explore the involvement of eukaryotic initiation factor 2alpha (eIF2alpha) kinase GCN2 and C/EBP homologous protein (CHOP) in this process.

Main Methods:

  • Treatment of SCC25 HNSCC cells and CHOP(-/-) and GCN2(-/-) murine embryonic fibroblasts (MEFs) with lovastatin.
  • Analysis of eIF2alpha phosphorylation, global protein translation, and expression of ATF4, ATF3, and CHOP.
  • Assessment of lovastatin's effect on proteasome activity.
  • Evaluation of apoptosis induction in response to lovastatin treatment in wild-type and knockout MEFs.

Main Results:

  • Lovastatin treatment induced eIF2alpha phosphorylation and inhibited global protein translation in SCC25 cells.
  • ATF4 expression was induced by lovastatin, followed by increased expression of its targets ATF3 and CHOP.
  • Lovastatin-induced apoptosis was attenuated in CHOP(-/-) and GCN2(-/-) MEFs, indicating a crucial role for CHOP and GCN2.
  • Lovastatin did not significantly affect proteasome activity, ruling out this mechanism for ISR activation.

Conclusions:

  • Lovastatin induces apoptosis in HNSCC cells through a novel mechanism involving the activation of the ISR.
  • The GCN2-eIF2alpha-ATF4 pathway, leading to CHOP expression, is critical for lovastatin-induced apoptosis.
  • Lovastatin acts as a potent inducer of the ISR by targeting mevalonate synthesis, independent of proteasome inhibition.

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