DNA damaging drugs-induced down-regulation of Bcl-2 is essential for induction of apoptosis in high-risk HPV-positive HEp-2 and KB cells

Cancer Lett. 2006 May 18;236(2):213-21. doi: 10.1016/j.canlet.2005.05.024. Epub 2005 Jul 5.

Abstract

DNA damaging chemotherapeutic agents like carboplatin (Carb) and 5-fluorouracil (5-FU), whose effects are mediated through diverse intracellular targets, induce apoptosis in various cancer cells including human papillomavirus (HPV) positive HEp-2 and KB cells. The present work reports the involvement of Bcl-2 in response to the exposure of HEp-2 and KB cells to Carb or 5-FU. We demonstrate that both these drugs are potent inducers of apoptosis. Apoptosis was preceded by decrease in Bcl-2 protein level accompanied by caspase-9 activation and poly(ADP-ribose) polymerase (PARP) cleavage without altering Bax expression. Further analysis revealed down-regulation of Bcl-2 mRNA as well as protein in drugs treated cells. Ectopic expression of Bcl-2 protected cells against drugs mediated DNA damage-induced apoptosis. Overall, data indicates that genotoxic stress leads to down-regulation of Bcl-2 in HEp-2 and KB cells, which plays a decisive role in the outcome of stress in these cells.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimetabolites, Antineoplastic / pharmacology*
  • Antineoplastic Agents / pharmacology*
  • Apoptosis*
  • Carboplatin / pharmacology*
  • Caspase 9
  • Caspases / metabolism*
  • Cell Line, Tumor / drug effects
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Down-Regulation
  • Enzyme Activation / drug effects
  • Fluorouracil / pharmacology*
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • KB Cells
  • Papillomaviridae*
  • Papillomavirus Infections / drug therapy*
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Poly(ADP-ribose) Polymerases / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • RNA, Messenger / metabolism
  • Transfection

Substances

  • Antimetabolites, Antineoplastic
  • Antineoplastic Agents
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Messenger
  • Carboplatin
  • Poly(ADP-ribose) Polymerases
  • CASP9 protein, human
  • Caspase 9
  • Caspases
  • Fluorouracil