| First Author | Farhana L | Year | 2011 |
| Journal | Cell Death Differ | Volume | 18 |
| Issue | 1 | Pages | 164-73 |
| PubMed ID | 20671747 | Mgi Jnum | J:186337 |
| Mgi Id | MGI:5432059 | Doi | 10.1038/cdd.2010.84 |
| Citation | Farhana L, et al. (2011) Maximal adamantyl-substituted retinoid-related molecule-induced apoptosis requires NF-kappaB noncanonical and canonical pathway activation. Cell Death Differ 18(1):164-73 |
| abstractText | NF-kappaB 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-kappaB activation in prostate and breast carcinoma cells. Here, we show that 3-Cl-AHPC activated both IkappaB kinase (IKK)alpha and IKKbeta with subsequent activation of the canonical and noncanonical NF-kappaB pathways in the human breast carcinoma and leukemia cell lines. 3-Cl-AHPC-mediated activation of the NF-kappaB canonical pathway occurred within 6 h, whereas maximal activation of the NF-kappaB noncanonical pathway required 48 h. Knockout of IKKalpha or IKKbeta expression in mouse embryonic fibroblast cells and knockdown of IKKalpha or IKKbeta 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-kappaB-inducing kinase (NIK) expression, increased binding of NIK by TRAF3, activation of IKKalpha, 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 IKKalpha and IKKbeta by 3-Cl-AHPC. These findings suggest that NF-kappaB pathways have an important role in 3-Cl-AHPC-mediated apoptosis. |
