title: NF-κB p65 recruited SHP regulates PDCD5-mediated apoptosis in cancer cells.
abstract: Transcription factor NF-κB promotes cell proliferation in response to cell injury. Increasing evidence, however, suggests that NF-κB 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-κB pathways. The mechanism NF-κB uses to induce apoptosis remains largely unknown. NF-κB 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-κB 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-κB 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-κB p65, and found the SHP/NF-κB 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-κB p65 mediated apoptosis. Our results demonstrate a novel pathway for NF-κB p65 in regulating apoptosis through SHP and PDCD5.
authors.affiliation: Department of Oncology, John D Dingell VA Medical Center, 11M-HO, Room C3687, 4646 John R Street, Detroit, MI, 48201, USA.
authors.forename: Farhan
authors.initials: F
authors.lastname: Murshed
authors.forename: Lulu
authors.initials: L
authors.lastname: Farhana
authors.forename: Marcia I
authors.initials: MI
authors.lastname: Dawson
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Fontana
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002934:Cinnamates / Q000494:pharmacology*; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*
chemical_list: C480030:4-(3-(1-adamantyl)-4-hydroxyphenyl)-3-chlorocinnamic acid; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D002934:Cinnamates; D009363:Neoplasm Proteins; C117283:PDCD5 protein, human; D018160:Receptors, Cytoplasmic and Nuclear; D051996:Transcription Factor RelA; C099713:nuclear receptor subfamily 0, group B, member 2; D000218:Adamantane