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c-Jun NH2-terminal kinase-mediated up-regulation of death receptor 5 contributes to induction of apoptosis by the novel synthetic triterpenoid methyl-2-cyano-3,12-dioxooleana-1, 9-dien-28-oate in human lung cancer cells.
Cancer Res. 2004 Oct 15; 64(20):7570-8.CR

Abstract

Death receptor (DR) 4 or 5, on binding to its ligand, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), triggers apoptosis via activating the caspase-8-mediated caspase cascade. Certain anticancer drugs up-regulate the expression of these receptors and thereby induce apoptosis or enhance TRAIL-induced apoptosis. In this study, we explored the ability of methyl-2-cyano-3,12-dioxooleana-1,9-dien-28-oate (CDDO-Me) to activate the extrinsic DR-mediated apoptotic pathway in human lung cancer cells. We found that CDDO-Me not only activated caspase-8 but also induced expression of DRs, particularly DR5, in a p53-independent mechanism. Correspondingly, CDDO-Me augmented TRAIL-induced apoptosis in these cells regardless of p53 status as evidenced by enhanced DNA fragmentation and activation of caspase cascades, suggesting that CDDO-Me-induced DRs are functionally active. Moreover, silencing of DR5 expression using small interfering RNA suppressed apoptosis induced by CDDO-Me alone or by combination of CDDO-Me and TRAIL, indicating that DR5 up-regulation is required for induction of apoptosis by CDDO-Me and for enhancement of TRAIL-induced apoptosis by CDDO-Me. CDDO-Me rapidly activated c-Jun NH(2)-terminal kinase (JNK) before DR up-regulation and caspase-8 activation. Moreover, application of the JNK-specific inhibitor SP600125 blocked CDDO-Me-induced increases in JNK activation, DR up-regulation, caspase-8 activation, and DNA fragmentation. These results show that activation of JNK pathway results in CDDO-Me-induced DR up-regulation, caspase-8 activation, and apoptosis. Collectively, we conclude that CDDO-Me induces apoptosis via the JNK-mediated DR up-regulation in human lung cancer cells.

Authors+Show Affiliations

Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15492284

Citation

Zou, Wei, et al. "C-Jun NH2-terminal Kinase-mediated Up-regulation of Death Receptor 5 Contributes to Induction of Apoptosis By the Novel Synthetic Triterpenoid Methyl-2-cyano-3,12-dioxooleana-1, 9-dien-28-oate in Human Lung Cancer Cells." Cancer Research, vol. 64, no. 20, 2004, pp. 7570-8.
Zou W, Liu X, Yue P, et al. C-Jun NH2-terminal kinase-mediated up-regulation of death receptor 5 contributes to induction of apoptosis by the novel synthetic triterpenoid methyl-2-cyano-3,12-dioxooleana-1, 9-dien-28-oate in human lung cancer cells. Cancer Res. 2004;64(20):7570-8.
Zou, W., Liu, X., Yue, P., Zhou, Z., Sporn, M. B., Lotan, R., Khuri, F. R., & Sun, S. Y. (2004). C-Jun NH2-terminal kinase-mediated up-regulation of death receptor 5 contributes to induction of apoptosis by the novel synthetic triterpenoid methyl-2-cyano-3,12-dioxooleana-1, 9-dien-28-oate in human lung cancer cells. Cancer Research, 64(20), 7570-8.
Zou W, et al. C-Jun NH2-terminal Kinase-mediated Up-regulation of Death Receptor 5 Contributes to Induction of Apoptosis By the Novel Synthetic Triterpenoid Methyl-2-cyano-3,12-dioxooleana-1, 9-dien-28-oate in Human Lung Cancer Cells. Cancer Res. 2004 Oct 15;64(20):7570-8. PubMed PMID: 15492284.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - c-Jun NH2-terminal kinase-mediated up-regulation of death receptor 5 contributes to induction of apoptosis by the novel synthetic triterpenoid methyl-2-cyano-3,12-dioxooleana-1, 9-dien-28-oate in human lung cancer cells. AU - Zou,Wei, AU - Liu,Xiangguo, AU - Yue,Ping, AU - Zhou,Zhongmei, AU - Sporn,Michael B, AU - Lotan,Reuben, AU - Khuri,Fadlo R, AU - Sun,Shi-Yong, PY - 2004/10/20/pubmed PY - 2004/12/16/medline PY - 2004/10/20/entrez SP - 7570 EP - 8 JF - Cancer research JO - Cancer Res VL - 64 IS - 20 N2 - Death receptor (DR) 4 or 5, on binding to its ligand, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), triggers apoptosis via activating the caspase-8-mediated caspase cascade. Certain anticancer drugs up-regulate the expression of these receptors and thereby induce apoptosis or enhance TRAIL-induced apoptosis. In this study, we explored the ability of methyl-2-cyano-3,12-dioxooleana-1,9-dien-28-oate (CDDO-Me) to activate the extrinsic DR-mediated apoptotic pathway in human lung cancer cells. We found that CDDO-Me not only activated caspase-8 but also induced expression of DRs, particularly DR5, in a p53-independent mechanism. Correspondingly, CDDO-Me augmented TRAIL-induced apoptosis in these cells regardless of p53 status as evidenced by enhanced DNA fragmentation and activation of caspase cascades, suggesting that CDDO-Me-induced DRs are functionally active. Moreover, silencing of DR5 expression using small interfering RNA suppressed apoptosis induced by CDDO-Me alone or by combination of CDDO-Me and TRAIL, indicating that DR5 up-regulation is required for induction of apoptosis by CDDO-Me and for enhancement of TRAIL-induced apoptosis by CDDO-Me. CDDO-Me rapidly activated c-Jun NH(2)-terminal kinase (JNK) before DR up-regulation and caspase-8 activation. Moreover, application of the JNK-specific inhibitor SP600125 blocked CDDO-Me-induced increases in JNK activation, DR up-regulation, caspase-8 activation, and DNA fragmentation. These results show that activation of JNK pathway results in CDDO-Me-induced DR up-regulation, caspase-8 activation, and apoptosis. Collectively, we conclude that CDDO-Me induces apoptosis via the JNK-mediated DR up-regulation in human lung cancer cells. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/15492284/c_Jun_NH2_terminal_kinase_mediated_up_regulation_of_death_receptor_5_contributes_to_induction_of_apoptosis_by_the_novel_synthetic_triterpenoid_methyl_2_cyano_312_dioxooleana_1_9_dien_28_oate_in_human_lung_cancer_cells_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=15492284 DB - PRIME DP - Unbound Medicine ER -