The anti-obesity drug orlistat promotes sensitivity to TRAIL by two different pathways in hormone-refractory prostate cancer cells

Int J Oncol. 2012 May;40(5):1483-91. doi: 10.3892/ijo.2012.1353. Epub 2012 Feb 2.


The administration of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is one of the expected cancer therapeutics. However, improvements are required in therapies against TRAIL-resistant tumor cells. We report, here, that the anti-obesity drug orlistat enhances the sensitivity to TRAIL in hormone-refractory prostate cancer (HRPC) cells through two different pathways. The combination of orlistat and TRAIL remarkably induced apoptosis in TRAIL-resistant HRPC, DU145 and PC3 cells. Orlistat induced the expression of death receptor (DR) 5, which is one of the TRAIL receptors, at both the mRNA and protein levels. The suppression of DR5 with siRNA reduced the apoptosis induced by the combination of orlistat and TRAIL, suggesting that the apoptosis was at least partially due to the upregulation of DR5. Although the upregulation by orlistat of CHOP at both mRNA and protein levels was observed in both cell lines, the activation of the DR5 promoter in DU145 cells was CHOP-dependent, but that in PC3 cells was CHOP-independent. Moreover, orlistat induced reactive oxygen species (ROS), and a ROS scavenger diminished the sensitivity to TRAIL through the suppression of CHOP and DR5 expression in both cell lines. These results suggest that there are two pathways of upregulation of DR5 by orlistat, which are the ROS-CHOP pathway and the ROS-direct pathway. In conclusion, orlistat promotes the sensitivity to TRAIL by ROS-mediated pathways in prostate cancer cells, especially in TRAIL-resistant cells. We believe that the combination of orlistat and TRAIL in HRPC is promising as a new chemotherapeutic strategy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Obesity Agents / pharmacology
  • Antineoplastic Agents, Hormonal / therapeutic use*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Apoptosis / drug effects*
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm*
  • Free Radical Scavengers / pharmacology
  • Humans
  • Lactones / pharmacology
  • Male
  • Orlistat
  • Promoter Regions, Genetic / drug effects
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • RNA Interference
  • RNA, Messenger / metabolism
  • Reactive Oxygen Species / metabolism
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / drug effects
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / genetics
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism
  • Recombinant Proteins / pharmacology
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology
  • Transcription Factor CHOP / genetics
  • Transcription Factor CHOP / metabolism
  • Transfection
  • Up-Regulation


  • Anti-Obesity Agents
  • Antineoplastic Agents, Hormonal
  • DDIT3 protein, human
  • Free Radical Scavengers
  • Lactones
  • RNA, Messenger
  • Reactive Oxygen Species
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Recombinant Proteins
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Transcription Factor CHOP
  • Orlistat