Increased Resistance to Trail-Induced Apoptosis in Prostate Cancer Cells Selected in the Presence of Bicalutamide

Prostate. 2007 Aug 1;67(11):1194-201. doi: 10.1002/pros.20584.

Abstract

Background: Following prolonged treatment with the non-steroidal anti-androgen bicalutamide (Casodex), LNCaP cells have become resistant to this drug. Previously, we found that the bicalutamide-refractory subline LNCaP-Bic acquires a growth advantage and does not respond to androgenic stimulation. In the present study, we have asked whether changes in response to the tumor-selective apoptosis inducer TNF-related apoptosis-inducing ligand (TRAIL) occur in LNCaP-Bic cells.

Methods: LNCaP and LNCaP-Bic cells were incubated with increasing concentrations of TRAIL and apoptosis rate was analyzed using FACS. Expression of death receptors (DR), adaptor protein Fas-associated death domain (FADD), members of the Bcl-2 family, and caspases were investigated by Western blot.

Results: The percentage of cells undergoing apoptosis was lower in LNCaP-Bic in comparison to LNCaP cells. There were no major differences in death receptor expression between control LNCaP and bicalutamide-selected cells. Surprisingly, treatment with TRAIL increased the levels of Bcl-2 by 50% in LNCaP-Bic cells. The ratio cleaved caspase/procaspase-8 was substantially lower in LNCaP-Bic cells.

Conclusions: Reduced sensitivity to TRAIL-induced apoptosis is a novel mechanism relevant to resistance to bicalutamide in prostate cancer. Inability of TRAIL to cause programmed cell death might be caused by multiple perturbations in the TRAIL-signaling pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgen Antagonists / pharmacology*
  • Anilides / pharmacology*
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects*
  • Caspases / analysis
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • Humans
  • Male
  • Nitriles / pharmacology*
  • Prostatic Neoplasms / chemistry
  • Prostatic Neoplasms / pathology*
  • Proto-Oncogene Proteins c-bcl-2 / analysis
  • Receptors, Death Domain / analysis
  • Receptors, Death Domain / drug effects
  • TNF-Related Apoptosis-Inducing Ligand / administration & dosage
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology*
  • Tosyl Compounds / pharmacology*
  • bcl-2-Associated X Protein / analysis

Substances

  • Androgen Antagonists
  • Anilides
  • Antineoplastic Agents
  • Nitriles
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, Death Domain
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Tosyl Compounds
  • bcl-2-Associated X Protein
  • bicalutamide
  • Caspases