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Involvement of both endoplasmic reticulum- and mitochondria-dependent pathways in cardiotoxin III-induced apoptosis

Ching-Ming Chien1, Sheng-Huei Yang, Long-Sen Chang

  • 1Faculty of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung, Taiwan.

Clinical and Experimental Pharmacology & Physiology
|May 29, 2008
PubMed

Insights

Cardiotoxin III from cobra venom triggers cancer cell death through both endoplasmic reticulum stress and mitochondrial pathways. This research reveals dual mechanisms for CTX III

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Background:

  • Cardiotoxin (CTX) III, a polypeptide from Naja naja atra venom, exhibits potential anticancer properties.
  • Understanding the precise mechanisms of CTX III's action is crucial for its therapeutic development.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which Cardiotoxin III induces apoptosis in human leukaemia (HL-60) cells.
  • To investigate the roles of the endoplasmic reticulum (ER) stress and mitochondrial pathways in CTX III-mediated cell death.

Main Methods:

  • Induction of apoptosis in HL-60 cells using Cardiotoxin III.
  • Measurement of intracellular calcium and Grp78 levels to assess ER stress.
  • Analysis of mitochondrial apoptotic markers, including Bax/Bcl-2 ratio and cytochrome c release.
  • Inhibition studies using specific caspase inhibitors (caspase 12 and caspase 9 inhibitors).

Main Results:

  • CTX III activated the ER pathway, indicated by increased calcium and Grp78, leading to micro-calpain and caspase 12 activation.
  • CTX III also initiated the mitochondrial pathway, evidenced by an elevated Bax/Bcl-2 ratio, cytochrome c release, and caspase 9 activation.
  • Inhibitor studies showed that CTX III-induced caspase 9 and caspase 3 activation were significantly reduced by caspase 9 inhibition, but not by caspase 12 inhibition.
  • Caspase 12 activation was independent of caspase 9 activation.

Conclusions:

  • Cardiotoxin III induces apoptosis in HL-60 cells through a dual mechanism involving both ER stress and the mitochondrial apoptotic pathway.
  • The ER stress pathway, involving caspase 12, and the mitochondrial pathway, involving caspase 9, operate independently in CTX III-induced apoptosis.
  • These findings provide a comprehensive understanding of CTX III's anticancer effects, highlighting its potential as a therapeutic agent.

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