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Activation of Nuclear Factor-B Contributes to Induction of Death Receptors and Apoptosis by the Synthetic Retinoid CD437 in DU145 Human Prostate Cancer Cells

Departments of ¹ Urology and ² Hematology and Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia and ³ Department of Thoracic/Head and Neck Medical Oncology, M.D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Shi-Yong Sun, Department of Hematology and Oncology, Winship Cancer Institute, Emory University School of Medicine, 1365-C Clifton Road, C3088, Atlanta, GA 30322. Phone: 404-778-2170; Fax: 404-778-5520; E-mail: shi-yong_sun{at}emory.org.

Activation of the transcription factor, nuclear factor-B (NF-B), results in up-regulation of not only antiapoptotic genes but also proapoptotic genes, including death receptor 4 (DR4) and death receptor 5 (DR5). Therefore, NF-B activation either suppresses or promotes apoptosis depending on the type of stimulus or cell context. We showed previously that the synthetic retinoid, 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437), effectively induces apoptosis particularly in androgen-independent prostate carcinoma cells. This effect was associated with the ability of CD437 to induce the expression of DR4 and DR5. In the present study, we examined the hypothesis that NF-B activation plays a role in CD437-induced death receptor expression and apoptosis. Treatment of DU145 cells with CD437 resulted in a rapid decrease (3 hours) of IB, which was accompanied by increased translocation of the NF-B subunit p65 from the cytoplasm to the nucleus and increased NF-B DNA-binding activity (4 hours). The NF-B inhibitor, helenalin, inhibited CD437-induced IB reduction and p65 nuclear translocation. Accordingly, it also abrogated CD437-induced up-regulation of DR4, activation of caspase-8 and caspase-3, and increased DNA fragmentation. Overexpression of an IB dominant-negative mutant blocked not only CD437-induced p65 nuclear translocation but also DR4 up-regulation, caspase activation, and DNA fragmentation. CD437 was unable to decrease IB protein levels and up-regulate DR4 expression in CD437-resistant DU145 cells. Moreover, knockdown of Fas-associated death domain, caspase-8, and DR4, respectively, suppressed CD437-induced apoptosis. Collectively, these results indicate that CD437 activates NF-B via decreasing IB protein and thereby induces DR4 expression and subsequent apoptosis in DU145 cells.

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