Peroxide is a key mediator of Bcl-2 down-regulation and apoptosis induction by cisplatin in human lung cancer cells

Liying Wang, Pithi Chanvorachote, David Toledo, Christian Stehlik, Robert R. Mercer, Vincent Castranova, Yon Rojanasakul*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

54 Scopus citations

Abstract

Susceptibility to apoptosis is an essential prerequisite for successful eradication of tumor cells by chemotherapy. Consequently, resistance to apoptosis has been established as one of the mechanisms responsible for the failure of therapeutic approaches in many types of cancers. In the present study, we investigated the susceptibility of human lung cancer H460 cells to apoptotic cell death induced by cisplatin and determined its regulatory mechanisms. Treatment of the cells with cisplatin induced rapid generation of multiple oxidative species and a concomitant increase in apoptotic cell death. Apoptosis induced by cisplatin was mediated through the mitochondrial death pathway, which requires caspase-9 activation and is regulated by Bcl-2. Cisplatin induced down-regulation of Bcl-2 through a process that involves dephosphorylation and ubiquitination of the protein, which facilitates its degradation by proteasome. This down-regulation was inhibited by antioxidant enzymes catalase and glutathione peroxidase (H2O2 scavenger), but not by superoxide dismutase (O2-. scavenger) or deferoxamine (OH. inhibitor). Electron spin resonance and flow cytometric analyses showed the formation of H2O2 along with O2-. and OH. radicals after cisplatin treatment. H2O2 was generated in part by dismutation of O 2-. and served as a precursor for OH.. Together, our results indicate an essential role of H2O2 in the regulation of Bcl-2 and apoptotic cell death induced by cisplatin. Because aberrant expression of Bcl-2 has been associated with death resistance of cancer cells to chemotherapy, the results of this study could be used to aid the design of more effective strategies for cancer treatment.

Original languageEnglish (US)
Pages (from-to)119-127
Number of pages9
JournalMolecular pharmacology
Volume73
Issue number1
DOIs
StatePublished - Jan 2008

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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