Androgens regulate TRAIL-induced cell death in prostate cancer cells via multiple mechanisms

Cancer Lett. 2013 Jul 10;335(1):136-44. doi: 10.1016/j.canlet.2013.02.001. Epub 2013 Feb 9.

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising therapeutic agent for prostate cancer because it selectively induces apoptosis in cancer cells but not in normal cells. Previous reports have suggested that androgens regulate TRAIL-induced apoptosis in prostate cancer cells. However, there are discrepancies between these reports of how androgens affect TRAIL-induced cell death. To clarify the role of androgens on TRAIL-induced apoptosis in prostate cancer cells, we investigated the effects of androgen on TRAIL-induced cell death in a dose-response manner. Our results showed that although androgens sensitize LNCaP cells to TRAIL-induced apoptosis, this effect is dose-dependent and biphasic. We found that low levels of androgen are superior to high levels of androgen in term of sensitizing LNCaP cells to TRAIL. We also found that upregulation of DR5 (TRAIL-R2) expression by androgens is critical for sensitizing LNCaP cells to TRAIL. However, low levels of androgen are sufficient to induce DR5 expression and sensitize LNCaP cells to TRAIL-induced cell death. High levels of androgen alter the TRADD/RIP1 ratio, which may contribute to NF-κB activation and sequentially inhibit TRAIL-induced apoptosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androstadienes / pharmacology
  • Antineoplastic Agents / pharmacology*
  • Apoptosis
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Gene Expression Regulation / drug effects
  • Humans
  • Male
  • Metribolone / pharmacology*
  • NF-kappa B / metabolism
  • Nuclear Pore Complex Proteins / metabolism
  • Prostatic Neoplasms
  • RNA-Binding Proteins / metabolism
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism
  • Signal Transduction / drug effects
  • TNF Receptor-Associated Death Domain Protein / metabolism
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology*
  • Testosterone Congeners / pharmacology*
  • Testosterone Congeners / physiology
  • Wortmannin

Substances

  • AGFG1 protein, human
  • Androstadienes
  • Antineoplastic Agents
  • NF-kappa B
  • Nuclear Pore Complex Proteins
  • RNA-Binding Proteins
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • TNF Receptor-Associated Death Domain Protein
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFRSF10A protein, human
  • Testosterone Congeners
  • Metribolone
  • Wortmannin