Maximal adamantyl-substituted retinoid-related molecule-induced apoptosis requires NF- B noncanonical and canonical pathway activation

• Published in: Cell death and differentiation 2011-01, Vol.18 (1), p.164-173
• Main Authors: Farhana, L, Dawson, M I, Murshed, F, Fontana, J A
• Format: Article
• Language: English
• Subjects: Apoptosis; Breast cancer; Cell death; Kinases; Leukemia; Prostate; Proteins; Tumor necrosis factor-TNF
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2010.84

NF-κB transcription factors have a critical role in regulating cell survival and apoptosis. We have previously shown that 4-(3-Cl-(1-adamantyl)-4-hydroxyphenyl)-3-chlorocinnamic acid (3-Cl-AHPC), an adamantyl-substituted retinoid molecule, induced apoptosis and required NF-κB activation in prostate and breast carcinoma cells. Here, we show that 3-Cl-AHPC activated both IκB kinase (IKK)α and IKK[beta] with subsequent activation of the canonical and noncanonical NF-κB pathways in the human breast carcinoma and leukemia cell lines. 3-Cl-AHPC-mediated activation of the NF-κB canonical pathway occurred within 6h, whereas maximal activation of the NF-κB noncanonical pathway required 48h. Knockout of IKKα or IKK[beta] expression in mouse embryonic fibroblast cells and knockdown of IKKα or IKK[beta] in MDA-MB-468 cells resulted in the inhibition of 3-Cl-AHPC-mediated apoptosis, indicating that activation of canonical and noncanonical pathways are required for maximal 3-Cl-AHPC-mediated apoptosis. 3-Cl-AHPC activation of the noncanonical pathway was preceded by caspase-mediated decrease in the E3-ligase c-IAP1 with subsequent stabilization of NF-κB-inducing kinase (NIK) expression, increased binding of NIK by TRAF3, activation of IKKα, and the resultant increased levels of RelB and p52. Increased expression of c-IAP1 blocked 3-Cl-AHPC-mediated stabilization of NIK levels and 3-Cl-AHPC-mediated apoptosis. Cdc37 expression was required for activation of IKKα and IKK[beta] by 3-Cl-AHPC. These findings suggest that NF-κB pathways have an important role in 3-Cl-AHPC-mediated apoptosis.