Involvement of proapoptotic Bcl-2 family members in parthenolide-induced mitochondrial dysfunction and apoptosis

Siyuan Zhang, Choon Nam Ong, Han Ming Shen

Research output: Contribution to journalArticlepeer-review

76 Scopus citations

Abstract

Parthenolide is a sesquiterpene lactone responsible for the bioactivities of Feverfew. Besides its potent anti-inflammatory effect, this compound has recently been reported to induce apoptosis in cancer cells, possibly through mitochondrial dysfunction. In the present study, we attempted to examine parthenolide-mediated cell death signaling pathway by focusing on the involvement of Bcl-2 family members. Using a human colorectal cancer cell line COLO205, we first demonstrated that parthenolide acted through the cell death receptor pathway to activate caspase 8. Following caspase 8 activation, Bid, a proapoptotic Bcl-2 member, was cleaved and this cleavage then triggered Bax conformational changes and Bax translocation from cytosol to mitochondrial membrane. Meanwhile, another proapoptotic protein, Bak, was up-regulated and oligomerized on the mitochondrial membrane. All these alterations were found to be prerequisite for the subsequent release of proapopototic mitochondrial proteins, including cytochrome c and Samc, in parthenolide-treated cells. Moreover, selective inhibition of caspase 8 activity by a synthetic caspase inhibitor (IETD-FMK) or overexpression of a viral protein (CrmA) suppressed the cleavage of Bid, conformational changes of Bax, cytochrome c release, and apoptosis. Therefore, the proapoptotic Bcl-2 family members are important mediators relaying the cell death signaling elicited by parthenolide from caspase 8 to downstream effector caspases such as caspase 3, and eventually to cell death.

Original languageEnglish (US)
Pages (from-to)175-188
Number of pages14
JournalCancer Letters
Volume211
Issue number2
DOIs
StatePublished - Aug 10 2004
Externally publishedYes

Keywords

  • Apoptosis
  • Bcl-2 family
  • Mitochondria
  • PARP, poly(ADP-ribose)polymerase
  • Parthenolide
  • PN, parthenolide
  • Z-IETD-FMK, benzyloxycarbonyl-Ile-Glu-Thr-Asp-(OMe) fluoromethyl ketone
  • z-VAD-FMK, benzyloxycarbonyl-Val-Ala-Asp-(OMe) fluoromethyl ketone

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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