Bcl-2-mediated potentiation of neocarzinostatin-induced apoptosis: Requirement for caspase-3, sulfhydryl groups, and cleavable Bcl-2

Zhiping Mi, Borah Hong, Zeljka Korade Mirnics, Yulia Y. Tyurina, Valerian E. Kagan, Ye Liang, Nina Felice Schor

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Overexpression of antiapoptotic Bcl-2 family members is thought to contribute to chemotherapeutic resistance of neural crest tumors. Paradoxical potentiation by Bcl-2 of apoptosis induced by the antineoplastic prodrug, neocarzinostatin (NCS), has been observed in PC12 pheochromocytoma cells. Prior studies have indicated that the cleavage of Bcl-2 to its proapoptotic counterpart mediated by caspase-3 is responsible for this potentiation of apoptosis. This has led to the hypothesis that induction of caspase-3 expression in bcl-2-transfected, caspase-3-deficient MCF-7 cells, will result in Bcl-2 cleavage and Bcl-2-dependent potentiation of NCS-induced apoptosis. These studies have further led to the hypothesis that both cleavable Bcl-2 and sulfhydryl groups are required for the activity of caspase-3 in this regard. As hypothesized, co-transfection of bcl-2- transfected MCF-7 cells with a caspase-3 expression construct results in cleavage of Bcl-2 and potentiation of dose-dependent, NCS-mediated cell death. Furthermore, PC12 cells transfected with an expression construct for cleavage-resistant Bcl-2 demonstrated attenuated potentiation of apoptosis relative to their counterparts transfected with wild-type bcl-2. Finally, irreversible oxidative titration of sulfhydryl groups resulted in concentration-dependent attenuation of apoptosis in PC12 cells, along with prevention of caspase- 3 activation and Bcl-2 cleavage. These results definitively demonstrate the requirement for caspase-3, cleavable Bcl-2, and available sulfhydryl groups (separate from those required for NCS activation) in potentiation of NCS-induced apoptosis by Bcl-2.

Original languageEnglish (US)
Pages (from-to)357-367
Number of pages11
JournalCancer Chemotherapy and Pharmacology
Volume57
Issue number3
DOIs
StatePublished - Mar 1 2006
Externally publishedYes

Keywords

  • Apoptosis
  • Caspase-3
  • Chemotherapeutic agent
  • Enediyne
  • Reduced glutathione

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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