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Bortezomib induces autophagy in head and neck squamous cell carcinoma cells via JNK activation

Changyou Li1, Daniel E Johnson

  • 1Department of Medicine, University of Pittsburgh and the University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.

Cancer Letters
|October 14, 2011
PubMed

Insights

Proteasome inhibitor bortezomib triggers autophagy in head and neck cancer cells. This process requires jun N-terminal kinase (JNK) signaling, highlighting a key molecular mechanism for autophagy induction.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Oncology

Background:

  • The precise molecular mechanisms driving autophagy induction upon proteasome inhibition remain incompletely elucidated.
  • Autophagy plays a critical role in cellular homeostasis and stress response, particularly in cancer cells.
  • Proteasome inhibitors are utilized in cancer therapy, making their effects on cellular processes like autophagy a significant area of study.

Purpose of the Study:

  • To investigate the molecular pathways responsible for autophagy induction by the proteasome inhibitor bortezomib in head and neck squamous cell carcinoma (HNSCC) cells.
  • To determine the role of specific signaling pathways, such as jun N-terminal kinase (JNK) and p38 MAPK, in bortezomib-induced autophagy.
  • To elucidate the relationship between proteasome inhibition, JNK activation, and the regulation of autophagy.

Main Methods:

  • Treatment of HNSCC cells with bortezomib.
  • Assessment of autophagy by monitoring autophagosome formation and autophagic flux.
  • Analysis of protein phosphorylation, specifically the activation of jun N-terminal kinase (JNK) and p38 MAPK.
  • Pharmacological inhibition of JNK and p38 MAPK pathways to evaluate their necessity in bortezomib's effects.
  • Western blot analysis to detect autophagy-related proteins and phosphorylated Bcl-2.

Main Results:

  • Bortezomib treatment robustly induced autophagy, evidenced by increased autophagosome formation and complete autophagic flux in HNSCC cells.
  • Bortezomib induced the phosphorylation and activation of jun N-terminal kinase (JNK) enzymes.
  • JNK activation led to the phosphorylation of Bcl-2 at serine 70, a known regulator of autophagy.
  • Pharmacological inhibition of JNK, but not p38 MAPK, significantly attenuated the induction of autophagy regulatory proteins and autophagosome formation by bortezomib.

Conclusions:

  • Jun N-terminal kinase (JNK) signaling is essential for the induction of autophagy by the proteasome inhibitor bortezomib in HNSCC cells.
  • Bortezomib activates autophagy through a JNK-dependent pathway involving the phosphorylation of Bcl-2.
  • These findings clarify a critical molecular mechanism linking proteasome inhibition to autophagy activation, with implications for cancer therapy.

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