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Bortezomib/proteasome inhibitor triggers both apoptosis and autophagy-dependent pathways in melanoma cells

Denis Selimovic1, Benjamin B O W Porzig, Abdelouahid El-Khattouti

  • 1Institut National de la Santé et de la Recherche Médicale, U 977, France.

Cellular Signalling
|October 20, 2012
PubMed

Insights

Bortezomib induces apoptosis and autophagy in melanoma cells by activating endoplasmic reticulum stress and mitochondrial pathways. This study elucidates the molecular mechanisms behind bortezomib

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Endoplasmic reticulum (ER) stress and mitochondrial dysregulation are key targets for anticancer agents.
  • Bortezomib is a therapeutic agent with known anticancer properties.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which bortezomib induces apoptosis and autophagic formation in melanoma cells.
  • To investigate the roles of ER stress and mitochondrial pathways in bortezomib's effects.

Main Methods:

  • Treatment of melanoma cells with bortezomib.
  • Analysis of protein expression (Noxa, Mcl-1, HSP70, LC3).
  • Assessment of ER stress markers (intracellular Ca(2+) release) and mitochondrial pathways (ROS, AIF, cytochrome c).
  • Inhibition studies using caspase-3, ASK1, JNK, and HSP70 inhibitors.

Main Results:

  • Bortezomib induced apoptosis, ER stress, and autophagic formation in melanoma cells.
  • Key signaling pathways including IRE1α, ASK1, JNK, p38, and transcription factors were activated.
  • Mitochondrial dysregulation involved ROS accumulation, AIF and cytochrome c release, and caspase activation.
  • Inhibitor studies revealed distinct roles for caspase-3, ASK1, JNK, and HSP70 in modulating apoptosis and autophagy.

Conclusions:

  • Bortezomib triggers apoptosis and autophagic formation in melanoma cells through complex interplay of ER stress and mitochondrial dysregulation pathways.
  • The study provides novel insights into the molecular mechanisms of bortezomib action in melanoma.

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