The natural product honokiol preferentially inhibits cellular FLICE-inhibitory protein and augments death receptor-induced apoptosis

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Molecular Cancer Therapeutics 7, 2212-2223, July 1, 2008. doi:

10.1158/1535-7163.MCT-07-2409

The natural product honokiol preferentially inhibits cellular FLICE-inhibitory

protein and augments death receptor-induced apoptosis

Shruti M. Raja1, Shuzhen Chen1, Ping Yue1, M. Acker1, Lefkove2,

Jack L. Arbiser2, Fadlo R. Khuri1 and Shi-Yong Sun1

Departments of 1 Hematology and Medical Oncology and 2 Dermatology, Winship

Cancer Institute, Emory University School of Medicine, Atlanta, Georgia

Requests for reprints: Shi-Yong Sun, Winship Cancer Institute, Emory University

School of Medicine, 1365-C Clifton Road Northeast, C3088, Atlanta, GA 30322.

Phone: 404-778-2170; Fax: 404-778-5520. E-mail: ssun@...

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 shown 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, cellular

FLICE-inhibitory protein (c-FLIP) was the only one that was rapidly

down-regulated by honokiol in all of the tested cell lines. The down-regulation

of c-FLIP by honokiol could be prevented by the proteasome inhibitor MG132.

Moreover, honokiol increased c-FLIP ubiquitination. These results indicate that

honokiol down-regulates c-FLIP by facilitating its degradation through a

ubiquitin/proteasome-mediated mechanism. Enforced expression of ectopic c-FLIP

abolished the ability of honokiol to enhance TRAIL-induced apoptosis. Several

honokiol derivatives, which exhibited more potent effects on down-regulation 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 down-regulation is a key event for honokiol to modulate the death

receptor-induced apoptosis. [Mol Cancer Ther 2008;7(7):2212-23]

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Footnotes

Grant support: Georgia Cancer Coalition Distinguished Cancer Scholar award (S-Y.

Sun), Department of Defense grant W81XWH-04-1-0142-VITAL (S-Y. Sun for Project

4), NIH/National Cancer Institute Specialized Program of Research Excellence P50

grant CA128613-01 (S-Y. Sun for Project 2), NIH grant 5R01AR050727 (J.L.

Arbiser), Rabinowitch- Foundation and Minsk Foundation (J.L.

Arbiser), and Veterans Affairs Merit award (J.L. Arbiser).

The costs of publication of this article were defrayed in part by the payment of

page charges. This article must therefore be hereby marked advertisement in

accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Notes: S.M. Raja and S. Chen share equal first authorship. F.R. Khuri and S-Y.

Sun are Georgia Cancer Coalition Distinguished Cancer Scholars. This work was

part of S.M. Raja's honor thesis. S.M. Raja is currently a medical student at

Jefferson Medical College (Philadelphia, PA). T.M. Acker is a Ph.D. graduate

student in the Molecular and Systems Pharmacology Graduate Program at Emory

University.

3 Supplementary material for this article is available at Molecular Cancer

Therapeutics Online (http://mct.aacrjournals.org/).