Pim-1 knockdown potentiates paclitaxel-induced apoptosis in human hormone-refractory prostate cancers through inhibition of NHEJ DNA repair

Cancer Lett. 2012 Jun 28;319(2):214-222. doi: 10.1016/j.canlet.2012.01.004. Epub 2012 Jan 17.

Abstract

The knockdown of Pim-1 or inhibition of Pim-1 activity significantly increased γ-H2A.X expression. The effect was correlated to apoptosis and was attributed to the inhibition of nonhomologous DNA-end-joining (NHEJ) repair activity supported by the following observations: (1) inhibition of ATM and DNA-PKcs activities, (2) down-regulation of Ku expression and nuclear localization and (3) decrease of DNA end-binding of both Ku70 and Ku80. The data suggest that Pim-1 plays a crucial role in the regulation of NHEJ repair. In the absence of Pim-1, the ability of DNA repair significantly decreases when exposed to paclitaxel, leading to severe DNA damage and apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / genetics
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • DNA End-Joining Repair / drug effects*
  • DNA Helicases / metabolism
  • DNA-Binding Proteins / metabolism
  • Drug Resistance, Neoplasm / drug effects
  • Gene Knockdown Techniques
  • Histones / genetics*
  • Humans
  • Ku Autoantigen
  • Male
  • Microtubules / genetics
  • Paclitaxel / pharmacology*
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / genetics*
  • Proto-Oncogene Proteins c-pim-1 / antagonists & inhibitors
  • Proto-Oncogene Proteins c-pim-1 / genetics*

Substances

  • DNA-Binding Proteins
  • H2AX protein, human
  • Histones
  • PIM1 protein, human
  • Proto-Oncogene Proteins c-pim-1
  • DNA Helicases
  • XRCC5 protein, human
  • Ku Autoantigen
  • Paclitaxel