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

Abstract

Abstract. 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.

Anti‐Tumorigenic Potential of a Novel Orlistat‐AICAR Combination in Prostate Cancer Cells

“…AICAR has also been implicated in the potentiation of ROS production induced by high glucose levels in pancreatic beta cells [Kim et al, 2007]. Fujiwara et al reported that Orlistat induced ROS production in DU145 and PC3 PCa cells [Fujiwara et al, 2012]. We report here that a dose range of 0.5–3 mM of AICAR has non-significant effects on all three PCa cell lines tested (PC3, DU145, LNCaP) for a 24 h time point.…”

Myelopoietic Efficacy of Orlistat in Murine Hosts Bearing T Cell Lymphoma: Implication in Macrophage Differentiation and Activation

“…Consequently, one of the upcoming anticancer chemotherapeutic regimens depends on inhibition of FASN [10–14,16,17]. We and others have demonstrated that exposure of tumor cells to orlistat, a FASN inhibitor; can manifests tumor-specific cytotoxicity [18–22]. Moreover, impact of FASN inhibition on cell survival displays cell-specific variations [8].…”

Ethanolic extract of Descurainia sophia seeds sensitizes A549 human lung cancer cells to TRAIL cytotoxicity by upregulating death receptors

“…Biologically active phytochemicals isolated from medicinal plants or their crude extracts have been reported to enhance TRAIL-induced apoptosis via CHOP-dependent DR5 upregulation in cancer cells [ 21 , 29 ]. In addition to the CHOP-dependent pathway, CHOP-independent DR5 upregulation has been observed in certain cancer cells treated with TRAIL and other chemicals, such as Orlistat (Xenical TM ) [ 44 ] and curcumin [ 45 ], although the key mediators of DR5 upregulation have not been identified.…”