The Natural Product Honokiol Preferentially Inhibits c-FLIP and Augments Death Receptor-induced Apoptosis

• Type of Material: Article
• Authors: Shruti M. Raja, Emory University; Shuzhen Chen, Emory University; Ping Yue, Emory University; Timothy M. Acker, Emory University; Benjamin Lefkove, Emory University; Jack Arbiser, Emory University; Fadlo Khuri, Emory University; Shi-Yong Sun, Emory University
• Language: English
• Date: 2008-07
• Publisher: American Association for Cancer Research
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2008 American Association for Cancer Research
• Final Published Version (URL): http://mct.aacrjournals.org/content/7/7/2212.long
• Title of Journal or Parent Work: Molecular Cancer Therapeutics
• ISSN: 1535-7163
• Volume: 7
• Issue: 7
• Start Page: 2212
• End Page: 2223
• Grant/Funding Information: Georgia Cancer Coalition Distinguished Cancer Scholar award (to S-Y. S.), Department of Defense grant W81XWH-04-1-0142-VITAL (to S-Y. Sun for Project 4), NIH/NCI SPORE P50 grant CA128613-01 (to S-Y. Sun for Project 2), National Institute of Health grant 5R01AR050727 (to J.L. Arbiser), Jamie Rabinowitch-Davis Foundation and the Minsk Foundation (to J. L. Arbiser) and a VA Merit award (to J. L. Arbiser).
• Keywords: TRAIL; apoptosis; lung cancer; c-FLIP; death receptors; Honokiol
• Research Categories: Health Sciences, Pharmacology; Health Sciences, Oncology

Abstract

Targeting death receptor-mediated apoptosis has emerged as an effective strategy for cancer therapy. However, certain types of cancer cells are intrinsically resistant to death receptor-mediated apoptosis. In an effort to identify agents that can sensitize cancer cells to death receptor-induced apoptosis, we have identified Honokiol, a natural product with anticancer activity, as demonstrated in various preclinical studies, as an effective sensitizer of death receptor-mediated apoptosis. Honokiol alone moderately inhibited the growth of human lung cancer cells; however, when combined with tumor-necrosis factor-related apoptosis-inducing ligand (TRAIL), greater effects on decreasing cell survival and inducing apoptosis than TRAIL alone were observed, indicating that Honokiol cooperates with TRAIL to enhance apoptosis. This was also true to Fas-induced apoptosis when combined with Fas ligand or an agonistic anti-Fas antibody. Among several apoptosis-associated proteins tested, c-FLIP was the only one that was rapidly downregulated by Honokiol in all of the tested cell lines. The downregulation of c-FLIP by Honokiol could be prevented by the proteasome inhibitor MG132. Moreover, Honokiol increased c-FLIP ubiquitination. These results indicate that Honokiol downregulates c-FLIP by facilitating its degradation through a ubiquitin/proteasome-mediated mechanism. Enforced expression of ectopic c-FLIP abolished Honokiol’s ability to enhance TRAIL-induced apoptosis. Several Honokiol derivatives, which exhibited more potent effects on downregulation of c-FLIP than Honokiol, showed better efficacy than Honokiol in inhibiting the growth and enhancing TRAIL-induced apoptosis as well. Collectively, we conclude that c-FLIP downregulation is a key event for Honokiol to modulate the death receptor-induced apoptosis.