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Smac deficiency affects endoplasmic reticulum stress-induced apoptosis in human colon cancer cells

Qin He1, Jingxue Shi, Samantha Jones

  • 1Department of Pharmacology, State University of New York, Upstate Medical University, Syracuse, New York.

Molecular and Cellular Pharmacology
|September 28, 2011
PubMed

Insights

Thapsigargin induces endoplasmic reticulum stress and apoptosis. Smac deficiency impacts this process in colon cancer cells, affecting caspase activation and cytochrome c release, suggesting a Smac-cytochrome c signaling cross-talk.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Thapsigargin (TG) is a sesquiterpene lactone that inhibits ER calcium ATPases, disrupting calcium homeostasis and inducing ER stress.
  • TG previously shown to induce apoptosis via death receptor 5 (DR5) and intrinsic pathways.
  • Second mitochondrial-derived activator (Smac) modulates apoptosis by activating caspases through antagonizing inhibitors of apoptosis (IAPs).

Purpose of the Study:

  • Investigate the role of Smac deficiency in ER-stress-induced apoptosis in human colon cancer cells.
  • Determine the effect of Smac deficiency on TG-induced apoptosis signaling pathways.
  • Explore potential cross-talk between Smac and cytochrome c in ER stress response.

Main Methods:

  • Utilized Smac-proficient and Smac-deficient human colon cancer cell lines.
  • Administered Thapsigargin (TG) to induce ER stress and apoptosis.
  • Assessed DR5 upregulation, caspase activation (caspases 3, 9, 8), and cytochrome c release.

Main Results:

  • Smac deficiency significantly affected ER stress-induced apoptosis in colon cancer cells.
  • TG upregulated DR5 and activated caspases 3, 9, and 8 in Smac-proficient cells.
  • Smac deficiency impaired caspase activation but not DR5 upregulation; affected TG-induced cytochrome c release, indicating Smac-cytochrome c cross-talk.

Conclusions:

  • ER stress-induced apoptosis engages Smac for signal transduction in human colon cancer cells.
  • Smac deficiency modulates ER stress-induced apoptosis by affecting caspase activation and cytochrome c release.
  • A feedback signaling loop between Smac and cytochrome c may regulate the intrinsic apoptotic pathway during ER stress.

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