Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapeutic agent because of its tumor selectivity and its ability to induce apoptosis in cancer cells while sparing most normal cells. We evaluated whether docetaxel enhances TRAIL-mediated apoptosis in prostate cancer (PCa) cells and its mechanism.
LNCap-LN3, PC3, and DU 145 PCa cell lines were used to investigate the effects of TRAIL with docetaxel treatment (dosages, 1, 3, 5, and 10 nmol). To evaluate the mechanism, death receptor 4 (DR4), DR5, enhancer of zeste homolog 2 (EZH2) and E2F1 levels were assessed in PCa cells.
Hormone-sensitive LNCap-LN3 showed apoptosis in proportion to the concentration of docetaxel. Castration-resistant PC3 and DU 145 showed no change irrespective of the docetaxel concentration. However, combinations of docetaxel (2 nM) and TRAIL (100 ng/mL) had a significant effect on apoptosis of DU 145 cells. In DU 145 cells, docetaxel reduced EZH2 and elevated expression of DR4. The decrease of EZH2 by docetaxel was correlated with the E2F1 level, which was considered as the promoter of EZH2. DZNep reduced EZH2 and elevated DR4 in all PCa cells. Additionally, DZNep-enhanced TRAIL mediated reduction of PCa cell viability.
Docetaxel and the EZH2 inhibitor reduced EZH2 and elevated expression of DR4 in all PCa cell lines. Docetaxel-enhanced TRAIL mediated apoptosis in PCa via elevation of DR4 through epigenetic regulation by EZH2. To improve the efficacy of TRAIL for PCa treatment, adding docetaxel or EZH2 inhibitors to TRAIL may be promising.
The world journal of men's health. 2023 Jan 01 [Epub ahead of print]
Won Hyeok Lee, Seong Cheol Kim, Song Hee Kim, Ji Hyung Yoon, Kyung Hyun Moon, Sang Hyeon Cheon, Taekmin Kwon, Young Min Kim, Jeong Woo Park, Sang Hun Lee, Jeong Min Lee, Sungchan Park, Benjamin I Chung
Biomedical Research Center, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea., Department of Urology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea., Department of Pathology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea., School of Biological Sciences, University of Ulsan, Ulsan, Korea., Department of Obstetrics & Gynecology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea., Department of Urology, Stanford University Medical Center, Palo Alto, CA, USA.