This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shiraishi, T. Articles by Sakai, T. Search for Related Content PubMed PubMed Citation Articles by Shiraishi, T. Articles by Sakai, T.

Tunicamycin Enhances Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Induced Apoptosis in Human Prostate Cancer Cells

Departments of ¹ Molecular-Targeting Cancer Prevention and ² Urology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine; and ³ Department of Applied Biochemistry, Kyoto Prefectural University, Kyoto, Japan

Requests for reprints: Toshiyuki Sakai, Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan. Phone: 81-75-251-5339; Fax: 81-75-241-0792; E-mail: tsakai{at}koto.kpu-m.ac.jp.

Death receptor 5 (DR5/TRAIL-R2) is an apoptosis-inducing membrane receptor for tumor necrosis factor–related apoptosis–inducing ligand (TRAIL/Apo2L). In this study, we showed that tunicamycin, a naturally occurring antibiotic, is a potent enhancer of TRAIL-induced apoptosis through up-regulation of DR5 expression. Tunicamycin significantly sensitized PC-3, androgen-independent human prostate cancer cells, to TRAIL-induced apoptosis. The tunicamycin-mediated enhancement of TRAIL-induced apoptosis was markedly blocked by a recombinant human DR5/Fc chimeric protein. Tunicamycin and TRAIL cooperatively activated caspase-8, -10, -9, and -3 and Bid cleavage and this activation was also blocked in the presence of the DR5/Fc chimera. Tunicamycin up-regulated DR5 expression at the mRNA and protein levels in a dose-dependent manner. Furthermore, the tunicamycin-mediated sensitization to TRAIL was efficiently reduced by DR5 small interfering RNA, suggesting that the sensitization was mediated through induction of DR5 expression. Tunicamycin increased DR5 promoter activity and this enhanced activity was diminished by mutation of a CHOP-binding site. In addition, suppression of CHOP expression by small interfering RNA reduced the tunicamycin-mediated induction of DR5. Of note, tunicamycin-mediated induction of CHOP and DR5 protein expression was not observed in normal human peripheral blood mononuclear cells. Moreover, tunicamycin did not sensitize the cells to TRAIL-induced apoptosis. Thus, combined treatment with tunicamycin and TRAIL may be a promising candidate for prostate cancer therapy.

This article has been cited by other articles:

				J.-J. Chen, C.-W. Chou, Y.-F. Chang, and C.-C. Chen Proteasome Inhibitors Enhance TRAIL-Induced Apoptosis through the Intronic Regulation of DR5: Involvement of NF-{kappa}B and Reactive Oxygen Species-Mediated p53 Activation J. Immunol., June 15, 2008; 180(12): 8030 - 8039. [Abstract] [Full Text] [PDF]

				P. Lei, M. Abdelrahim, S. D. Cho, S. Liu, S. Chintharlapalli, and S. Safe 1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes inhibit colon cancer cell and tumor growth through activation of c-jun N-terminal kinase Carcinogenesis, June 1, 2008; 29(6): 1139 - 1147. [Abstract] [Full Text] [PDF]

				M. Lu, L. Xia, H. Hua, and Y. Jing Acetyl-Keto-{beta}-Boswellic Acid Induces Apoptosis through a Death Receptor 5-Mediated Pathway in Prostate Cancer Cells Cancer Res., February 15, 2008; 68(4): 1180 - 1186. [Abstract] [Full Text] [PDF]

				E. H. Kim, M. J. Yoon, S. U. Kim, T. K. Kwon, S. Sohn, and K. S. Choi Arsenic Trioxide Sensitizes Human Glioma Cells, but not Normal Astrocytes, to TRAIL-Induced Apoptosis via CCAAT/Enhancer-Binding Protein Homologous Protein Dependent DR5 Up-regulation Cancer Res., January 1, 2008; 68(1): 266 - 275. [Abstract] [Full Text] [PDF]

				L. H. Chen, C. C. Jiang, K. A. Kiejda, Y. F. Wang, R. F. Thorne, X. D. Zhang, and P. Hersey Thapsigargin sensitizes human melanoma cells to TRAIL-induced apoptosis by up-regulation of TRAIL-R2 through the unfolded protein response Carcinogenesis, November 1, 2007; 28(11): 2328 - 2336. [Abstract] [Full Text] [PDF]

				Q. Xu, N. Ohara, J. Liu, K. Nakabayashi, D. DeManno, K. Chwalisz, S. Yoshida, and T. Maruo Selective progesterone receptor modulator asoprisnil induces endoplasmic reticulum stress in cultured human uterine leiomyoma cells Am J Physiol Endocrinol Metab, October 1, 2007; 293(4): E1002 - E1011. [Abstract] [Full Text] [PDF]

				Y.-g. Son, E. H. Kim, J. Y. Kim, S. U. Kim, T. K. Kwon, A-R. Yoon, C.-O. Yun, and K. S. Choi Silibinin Sensitizes Human Glioma Cells to TRAIL-Mediated Apoptosis via DR5 Up-regulation and Down-regulation of c-FLIP and Survivin Cancer Res., September 1, 2007; 67(17): 8274 - 8284. [Abstract] [Full Text] [PDF]

				C. C. Jiang, L. H. Chen, S. Gillespie, K. A. Kiejda, N. Mhaidat, Y. F. Wang, R. Thorne, X. D. Zhang, and P. Hersey Tunicamycin Sensitizes Human Melanoma Cells to Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Induced Apoptosis by Up-regulation of TRAIL-R2 via the Unfolded Protein Response Cancer Res., June 15, 2007; 67(12): 5880 - 5888. [Abstract] [Full Text] [PDF]

				E. M. Jung, J.-W. Park, K. S. Choi, J.-W. Park, H. I. Lee, K.-S. Lee, and T. K. Kwon Curcumin sensitizes tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis through CHOP-independent DR5 upregulation Carcinogenesis, October 1, 2006; 27(10): 2008 - 2017. [Abstract] [Full Text] [PDF]

				P. Lei, M. Abdelrahim, and S. Safe 1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes inhibit ovarian cancer cell growth through peroxisome proliferator-activated receptor-dependent and independent pathways. Mol. Cancer Ther., September 1, 2006; 5(9): 2324 - 2336. [Abstract] [Full Text] [PDF]

				S. Nakata, T. Yoshida, T. Shiraishi, M. Horinaka, J. Kouhara, M. Wakada, and T. Sakai 15-Deoxy-{Delta}12,14-prostaglandin J2 induces death receptor 5 expression through mRNA stabilization independently of PPAR{gamma} and potentiates TRAIL-induced apoptosis. Mol. Cancer Ther., July 1, 2006; 5(7): 1827 - 1835. [Abstract] [Full Text] [PDF]