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Apoptosis Induction by a Novel Retinoid-Related Molecule Requires Nuclear Factor-B Activation

¹ John D Dingell Veterans Affairs Medical Center; ² Karmanos Cancer Institute and Department of Medicine, Wayne State University, Detroit, Michigan; and ³ The Burnham Institute, San Diego, California

Requests for reprints: Joseph A. Fontana, John D Dingell Veterans Affairs Medical Center, Oncology 11M-HO, Room C3687, 4646 John R. Street, Detroit, MI 48201. Phone: 313-576-3659; Fax: 313-576-1122; E-mail: joseph.fontana{at}med.va.gov.

Nuclear factor-B (NF-B) activation has been shown to be both antiapoptotic and proapoptotic depending on the stimulus and the specific cell type involved. NF-B activation has also been shown to be essential for apoptosis induction by a number of agents. The novel retinoid-related molecule 4-[3-Cl-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC) activates NF-B with subsequent apoptosis in a number of cell types. We have found that NF-B activation is essential for 3-Cl-AHPC–mediated apoptosis. 3-Cl-AHPC activates NF-B through IKK kinase activation and the subsequent degradation of IB. IKK kinase activation is associated with IKK-enhanced binding to HSP90. The HSP90 inhibitor geldanamycin enhances the degradation of IKK and blocks 3-Cl-AHPC activation of NF-B and 3-Cl-AHPC–mediated apoptosis. In addition, inhibition of IB degradation using a dominant-negative IB inhibits 3-Cl-AHPC–mediated apoptosis. NF-B p65 activation is essential for 3-Cl-AHPC apoptosis induction as evidenced by the fact that inhibition of p65 activation utilizing the inhibitor helenalin or loss of p65 expression block 3-Cl-AHPC–mediated apoptosis. NF-B has been shown to be antiapoptotic through its enhanced expression of a number of antiapoptotic proteins including X-linked inhibitor of apoptosis protein (XIAP), c-IAP1, and Bcl-X_L. Whereas exposure to 3-Cl-AHPC results in NF-B activation, it inhibits the expression of XIAP, c-IAP1, and Bcl-X_L and enhances the expression of proapoptotic molecules, including the death receptors DR4 and DR5 as well as Fas and Rip1. Thus, 3-Cl-AHPC, which is under preclinical development, has pleotrophic effects on malignant cells resulting in their apoptosis.

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