Activation of nuclear factor-kappaB contributes to induction of death receptors and apoptosis by the synthetic retinoid CD437 in DU145 human prostate cancer cells.

Abstract

Activation of the transcription factor, nuclear factor-kappaB (NF-kappaB), 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-kappaB 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-kappaB activation plays a role in CD437-induced death receptor expression and apoptosis. Treatment of DU145 cells with CD437 resulted in a rapid decrease (> or = 3 hours) of IkappaBalpha, which was accompanied by increased translocation of the NF-kappaB subunit p65 from the cytoplasm to the nucleus and increased NF-kappaB DNA-binding activity (> or = 4 hours). The NF-kappaB inhibitor, helenalin, inhibited CD437-induced IkappaBalpha 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 IkappaBalpha 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 IkappaBalpha 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-kappaB via decreasing IkappaBalpha protein and thereby induces DR4 expression and subsequent apoptosis in DU145 cells.

• Authors: Fengshuo Jin, Xiangguo Liu, Zhongmei Zhou, Ping Yue, Reuben Lotan, Fadlo R Khuri, Leland W K Chung, Shi-Yong Sun
• Journal: Cancer research (Cancer Res) Vol. 65 Issue 14 Pg. 6354-63 (Jul 15 2005) ISSN: 0008-5472 [Print] United States
• PMID: 16024638 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Antineoplastic Agents, Phytogenic
• CD 437
• I-kappa B Proteins
• NF-kappa B
• NFKBIA protein, human
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• Receptors, Tumor Necrosis Factor
• Retinoids
• Sesquiterpenes
• Sesquiterpenes, Guaiane
• TNFRSF10A protein, human
• TNFRSF10B protein, human
• NF-KappaB Inhibitor alpha
• helenalin
• CASP8 protein, human
• Caspase 8
• Caspases

Topics

• Antineoplastic Agents (pharmacology)
• Antineoplastic Agents, Phytogenic (pharmacology)
• Apoptosis (drug effects, physiology)
• Caspase 8
• Caspases (metabolism)
• Cell Line, Tumor
• Humans
• I-kappa B Proteins (biosynthesis, metabolism)
• Male
• NF-KappaB Inhibitor alpha
• NF-kappa B (antagonists & inhibitors, metabolism)
• Prostatic Neoplasms (drug therapy, metabolism, pathology)
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• Receptors, Tumor Necrosis Factor (biosynthesis)
• Retinoids (pharmacology)
• Sesquiterpenes (pharmacology)
• Sesquiterpenes, Guaiane
• Up-Regulation (drug effects)