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Article
Role of reactive oxygen species in proapoptotic ability of oncogenic H-Ras to increase human bladder cancer cell susceptibility to histone deacetylase inhibitor for caspase induction
Journal of Cancer Research and Clinical Oncology (2009)
  • SHAMBHUNATH CHOUDHARY, University of Tennessee - Knoxville
  • Hwa-Chain Robert Wang, University of Tennessee - Knoxville
Abstract

Reveal mechanisms for the novel proapoptotic ability of oncogenic H-Ras to increase cell susceptibility to a histone deacetylase inhibitor (HDACI) FR901228 for inducing caspase activation and selective apoptosis.

Methods

Human urinary bladder cancer J82 and oncogenic H-Ras-expressing J82 cells were used to reveal differential induction of intracellular reactive oxygen species (ROS), caspase activation, and apoptosis by HDACI FR901228. ROS levels and caspase-8, -9, and -3/7 activities were measured by flow cytometry and luminescence assays, respectively. Specific inhibitors were used to suppress caspases and ROS. Western blot analysis determined modulators of caspase pathways.

Results

ROS, caspase activity, and cell death was differentially increased by FR901228 in oncogenic H-Ras-expressing J82 versus parental cells. Blocking ROS resulted in reduced FR901228-induced cell death and caspase activation. Suppression of caspase-8 resulted in reduced FR901228-activated caspase-9 and -3/7. Suppression of caspase-9 resulted in reduced FR901228-activated caspase-3/7. Although FR901228 induced an ROS-dependent increase of FasL, FasL failed to induce caspase activation and cell death.

Conclusion

Increased ROS played an important role in the activation of the extrinsic and intrinsic caspase pathways to cooperatively induce executioner caspase-3/7 through a novel FasL-independent pathway in FR901228-induced selective apoptosis of oncogenic H-Ras-expressing J82 versus parental cells.

Keywords
  • caspase pathway,
  • Histone deacetylase inhibitor,
  • Proapoptotic H-Ras,
  • Reactive oxygen species,
  • Urinary bladder cancer cells
Publication Date
2009
Citation Information
SHAMBHUNATH CHOUDHARY and Hwa-Chain Robert Wang. "Role of reactive oxygen species in proapoptotic ability of oncogenic H-Ras to increase human bladder cancer cell susceptibility to histone deacetylase inhibitor for caspase induction" Journal of Cancer Research and Clinical Oncology Vol. 135 Iss. 11 (2009)
Available at: http://works.bepress.com/shambhunath_choudhary/4/