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 Shi, R.-X. Articles by Shen, H.-M. Search for Related Content PubMed PubMed Citation Articles by Shi, R.-X. Articles by Shen, H.-M.

Protein Kinase C Inhibition and X-Linked Inhibitor of Apoptosis Protein Degradation Contribute to the Sensitization Effect of Luteolin on Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Induced Apoptosis in Cancer Cells

Department of Community, Occupational, and Family Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Republic of Singapore

Requests for reprints: Han-Ming Shen, Department of Community, Occupational, and Family Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Singapore 117597, Republic of Singapore. Phone: 65-6874-4998; Fax: 65-6779-1489; E-mail: cofshm{at}nus.edu.sg.

Tumor necrosis factor (TNF)–related apoptosis-inducing ligand (TRAIL) is an important member of the TNF superfamily with great potential in cancer therapy. Luteolin is a dietary flavonoid commonly found in some medicinal plants. Here we found that pretreatment with a noncytotoxic concentration of luteolin significantly sensitized TRAIL-induced apoptosis in both TRAIL-sensitive (HeLa) and TRAIL-resistant cancer cells (CNE1, HT29, and HepG2). Such sensitization is achieved through enhanced caspase-8 activation and caspase-3 maturation. Further, the protein level of X-linked inhibitor of apoptosis protein (XIAP) was markedly reduced in cells treated with luteolin and TRAIL, and ectopic expression of XIAP protected against cell death induced by luteolin and TRAIL, showing that luteolin sensitizes TRAIL-induced apoptosis through down-regulation of XIAP. In search of the molecular mechanism responsible for XIAP down-regulation, we found that luteolin and TRAIL promoted XIAP ubiquitination and proteasomal degradation. Next, we showed that protein kinase C (PKC) activation prevented cell death induced by luteolin and TRAIL via suppression of XIAP down-regulation. Moreover, luteolin inhibited PKC activity, and bisindolylmaleimide I, a general PKC inhibitor, simulated luteolin in sensitizing TRAIL-induced apoptosis. Taken together, these results present a novel anticancer effect of luteolin and support its potential application in cancer therapy in combination with TRAIL. In addition, our data reveal a new function of PKC in cell death: PKC activation stabilizes XIAP and thus suppresses TRAIL-induced apoptosis.

This article has been cited by other articles:

				G. Gobbi, P. Mirandola, C. Carubbi, C. Micheloni, C. Malinverno, P. Lunghi, A. Bonati, and M. Vitale Phorbol ester-induced PKC{epsilon} down-modulation sensitizes AML cells to TRAIL-induced apoptosis and cell differentiation Blood, March 26, 2009; 113(13): 3080 - 3087. [Abstract] [Full Text] [PDF]

				C. Van Themsche, L. Lafontaine, and E. Asselin X-Linked Inhibitor of Apoptosis Protein Levels and Protein Kinase C Activity Regulate the Sensitivity of Human Endometrial Carcinoma Cells to Tumor Necrosis Factor{alpha}-Induced Apoptosis Endocrinology, August 1, 2008; 149(8): 3789 - 3798. [Abstract] [Full Text] [PDF]

				J. Zhou, G.-D. Lu, C.-S. Ong, C.-N. Ong, and H.-M. Shen Andrographolide sensitizes cancer cells to TRAIL-induced apoptosis via p53-mediated death receptor 4 up-regulation Mol. Cancer Ther., July 1, 2008; 7(7): 2170 - 2180. [Abstract] [Full Text] [PDF]

				S.-F. Yang, W.-E. Yang, H.-R. Chang, S.-C. Chu, and Y.-S. Hsieh Luteolin Induces Apoptosis in Oral Squamous Cancer Cells Journal of Dental Research, April 1, 2008; 87(4): 401 - 406. [Abstract] [Full Text] [PDF]

				W. Chen, X. Wang, J. Zhuang, L. Zhang, and Y. Lin Induction of death receptor 5 and suppression of survivin contribute to sensitization of TRAIL-induced cytotoxicity by quercetin in non-small cell lung cancer cells Carcinogenesis, October 1, 2007; 28(10): 2114 - 2121. [Abstract] [Full Text] [PDF]

				G. D. Lu, H.-M. Shen, M. C.M. Chung, and C. N. Ong Critical role of oxidative stress and sustained JNK activation in aloe-emodin-mediated apoptotic cell death in human hepatoma cells Carcinogenesis, September 1, 2007; 28(9): 1937 - 1945. [Abstract] [Full Text] [PDF]

				A. Ashare, M. M. Monick, A. B. Nymon, J. M. Morrison, M. Noble, L. S. Powers, T. O. Yarovinsky, T. L. Yahr, and G. W. Hunninghake Pseudomonas aeruginosa Delays Kupffer Cell Death via Stabilization of the X-Chromosome-Linked Inhibitor of Apoptosis Protein J. Immunol., July 1, 2007; 179(1): 505 - 513. [Abstract] [Full Text] [PDF]

				R. Shi, Q. Huang, X. Zhu, Y.-B. Ong, B. Zhao, J. Lu, C.-N. Ong, and H.-M. Shen Luteolin sensitizes the anticancer effect of cisplatin via c-Jun NH2-terminal kinase-mediated p53 phosphorylation and stabilization Mol. Cancer Ther., April 1, 2007; 6(4): 1338 - 1347. [Abstract] [Full Text] [PDF]

				J. Fang, Q. Zhou, X.-l. Shi, and B.-h. Jiang Luteolin inhibits insulin-like growth factor 1 receptor signaling in prostate cancer cells Carcinogenesis, March 1, 2007; 28(3): 713 - 723. [Abstract] [Full Text] [PDF]

				H. Sasaki, N. Ohara, Q. Xu, J. Wang, D. A. DeManno, K. Chwalisz, S. Yoshida, and T. Maruo A Novel Selective Progesterone Receptor Modulator Asoprisnil Activates Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL)-Mediated Signaling Pathway in Cultured Human Uterine Leiomyoma Cells in the Absence of Comparable Effects on Myometrial Cells J. Clin. Endocrinol. Metab., February 1, 2007; 92(2): 616 - 623. [Abstract] [Full Text] [PDF]

				N. Khan, F. Afaq, and H. Mukhtar Apoptosis by dietary factors: the suicide solution for delaying cancer growth Carcinogenesis, February 1, 2007; 28(2): 233 - 239. [Abstract] [Full Text] [PDF]

				T.-J. Lee, E. M. Jung, J. T. Lee, S. Kim, J.-W. Park, K. S. Choi, and T. K. Kwon Mithramycin A sensitizes cancer cells to TRAIL-mediated apoptosis by down-regulation of XIAP gene promoter through Sp1 sites. Mol. Cancer Ther., November 1, 2006; 5(11): 2737 - 2746. [Abstract] [Full Text] [PDF]

				H. S. Byun, K. A. Park, M. Won, K.-J. Yang, S. Shin, L. Piao, J. Y. Kwak, Z.-W. Lee, J. Park, J. H. Seok, et al. Phorbol 12-Myristate 13-Acetate Protects against Tumor Necrosis Factor (TNF)-Induced Necrotic Cell Death by Modulating the Recruitment of TNF Receptor 1-Associated Death Domain and Receptor-Interacting Protein into the TNF Receptor 1 Signaling Complex: Implication for the Regulatory Role of Protein Kinase C Mol. Pharmacol., September 1, 2006; 70(3): 1099 - 1108. [Abstract] [Full Text] [PDF]