Open AccessThe anti-obesity drug orlistat promotes sensitivity to TRAIL by two different pathways in hormone-refractory prostate cancer cells
Author(s) -
Junichi Fujiwara,
Yoshihiro Sowa,
Mano Horinaka,
Makoto Koyama,
Miki Wakada,
Tsuneharu Miki
Publication year - 2012
Publication title -
international journal of oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.405
H-Index - 122
ISSN - 1019-6439
DOI - 10.3892/ijo.2012.1353
Subject(s) - du145 , orlistat , apoptosis , cancer research , downregulation and upregulation , chop , prostate cancer , cancer , biology , pharmacology , medicine , endocrinology , lncap , biochemistry , weight loss , obesity , gene
The administration of tumor necrosis factor-related apoptosis-inducing ligand(TRAIL) is one of the expected cancer therapeutics. However, improvements arerequired in therapies against TRAIL-resistant tumor cells. We report, here, thatthe anti-obesity drug orlistat enhances the sensitivity to TRAIL in hormone-refractoryprostate cancer (HRPC) cells through two different pathways. The combination oforlistat and TRAIL remarkably induced apoptosis in TRAIL-resistant HRPC, DU145and PC3 cells. Orlistat induced the expression of death receptor (DR) 5, whichis one of the TRAIL receptors, at both the mRNA and protein levels. The suppressionof DR5 with siRNA reduced the apoptosis induced by the combination of orlistatand TRAIL, suggesting that the apoptosis was at least partially due to the upregulationof DR5. Although the upregulation by orlistat of CHOP at both mRNA and proteinlevels was observed in both cell lines, the activation of the DR5 promoter inDU145 cells was CHOP-dependent, but that in PC3 cells was CHOP-independent. Moreover,orlistat induced reactive oxygen species (ROS), and a ROS scavenger diminishedthe sensitivity to TRAIL through the suppression of CHOP and DR5 expression inboth cell lines. These results suggest that there are two pathways of upregulationof 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 pathwaysin prostate cancer cells, especially in TRAIL-resistant cells. We believe thatthe combination of orlistat and TRAIL in HRPC is promising as a new chemotherapeuticstrategy.