Apoptosis induction by a novel retinoid-related molecule requires nuclear factor-κB activation

• Published in: Cancer research (Chicago, Ill.) Ill.), 2005-06, Vol.65 (11), p.4909-4917
• Main Authors: FARHANA, Lulu, DAWSON, Marcia I, FONTANA, Joseph A
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Biological and medical sciences; Medical sciences; Pharmacology. Drug treatments; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-04-4124

Nuclear factor-κB (NF-κB) activation has been shown to be both antiapoptotic and proapoptotic depending on the stimulus and the specific cell type involved. NF-κB 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-κB with subsequent apoptosis in a number of cell types. We have found that NF-κB activation is essential for 3-Cl-AHPC–mediated apoptosis. 3-Cl-AHPC activates NF-κB through IKKα kinase activation and the subsequent degradation of IκBα. IKKα kinase activation is associated with IKKα-enhanced binding to HSP90. The HSP90 inhibitor geldanamycin enhances the degradation of IKKα and blocks 3-Cl-AHPC activation of NF-κB and 3-Cl-AHPC–mediated apoptosis. In addition, inhibition of IκBα degradation using a dominant-negative IκBα inhibits 3-Cl-AHPC–mediated apoptosis. NF-κB 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-κB 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-XL. Whereas exposure to 3-Cl-AHPC results in NF-κB activation, it inhibits the expression of XIAP, c-IAP1, and Bcl-XL 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.