NF-[kappa]B p65 recruited SHP regulates PDCD5-mediated apoptosis in cancer cells

• Published in: Apoptosis (London) 2014-03, Vol.19 (3), p.506
• Main Authors: Murshed, Farhan, Farhana, Lulu, Dawson, Marcia I, Fontana, Joseph A
• Format: Article
• Language: English
• ISSN: 1360-8185; 1573-675X
• DOI: 10.1007/s10495-013-0939-y

Transcription factor NF-[kappa]B promotes cell proliferation in response to cell injury. Increasing evidence, however, suggests that NF-[kappa]B can also play an apoptotic role depending on the stimulus and cell type. We have previously demonstrated that novel retinoid 4-[3-Cl-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC)-mediated apoptosis in breast carcinoma cells requires activation of canonical and non-canonical NF-[kappa]B pathways. The mechanism NF-[kappa]B uses to induce apoptosis remains largely unknown. NF-[kappa]B subunit p65 (RelA) was identified as one potent transcriptional activator in 3-Cl-AHPC-mediated apoptosis in cells. Here we used ChIP-on-chip to identify NF-[kappa]B p65 genes activated in 3-Cl-AHPC mediated apoptosis. This paper focuses on one hit: pro-apoptotic protein programmed cell death 5 (PDCD5). 3-Cl-AHPC mediated apoptosis in MDA-MB-468 had three related effects on PDCD5: NF-[kappa]B p65 binding to the PDCD5 gene, enhanced PDCD5 promoter activity, and increased PDCD5 protein expression. Furthermore, 3-Cl-AHPC increased orphan nuclear receptor small heterodimer partner (SHP) mRNA expression, increased SHP protein bound to NF-[kappa]B p65, and found the SHP/NF-[kappa]B p65 complex attached to the PDCD5 gene. PDCD5 triggered apoptosis through increased Bax protein and release of cytochrome C from mitochondria to cytosol. Lastly, knockdown of PDCD5 protein expression blocked 3-Cl-AHPC mediated apoptosis, while over-expression of PDCD5 enhanced apoptosis, suggesting PDCD5 is necessary and sufficient for NF-[kappa]B p65 mediated apoptosis. Our results demonstrate a novel pathway for NF-[kappa]B p65 in regulating apoptosis through SHP and PDCD5.[PUBLICATION ABSTRACT]