The anti-obesity drug orlistat promotes sensitivity to TRAIL by two             different pathways in hormone-refractory prostate cancer cells.
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.
Department of Molecular-Targeting Cancer Prevention, Graduate                     School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji,                     Kamigyo-ku, Kyoto 602-8566, Japan.
Jun
J
Fujiwara
Yoshihiro
Y
Sowa
Mano
M
Horinaka
Makoto
M
Koyama
Miki
M
Wakada
Tsuneharu
T
Miki
Toshiyuki
T
Sakai
D019440:Anti-Obesity Agents / Q000494:pharmacology; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D007783:Lactones / Q000494:pharmacology; D008297:Male; D000077403:Orlistat; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation
D019440:Anti-Obesity Agents; D018931:Antineoplastic Agents, Hormonal; C497249:DDIT3 protein, human; D016166:Free Radical Scavengers; D007783:Lactones; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D051742:Transcription Factor CHOP; D000077403:Orlistat