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

Abstract

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 IKKβ 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 6 h, whereas maximal activation of the NF-κB noncanonical pathway required 48 h. Knockout of IKKα or IKKβ expression in mouse embryonic fibroblast cells and knockdown of IKKα or IKKβ 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 IKKβ by 3-Cl-AHPC. These findings suggest that NF-κB pathways have an important role in 3-Cl-AHPC-mediated apoptosis.

• Authors: L Farhana, M I Dawson, F Murshed, J A Fontana
• Journal: Cell death and differentiation (Cell Death Differ) Vol. 18 Issue 1 Pg. 164-73 (Jan 2011) ISSN: 1476-5403 [Electronic] England
• PMID: 20671747 (Publication Type: Journal Article)

Chemical References

• 4-(3-(1-adamantyl)-4-hydroxyphenyl)-3-chlorocinnamic acid
• CDC37 protein, human
• Cell Cycle Proteins
• Cinnamates
• Inhibitor of Apoptosis Proteins
• NF-kappa B
• NF-kappa B p52 Subunit
• TNF Receptor-Associated Factor 3
• Transcription Factor RelB
• Protein Serine-Threonine Kinases
• I-kappa B Kinase
• NF-kappa B kinase
• Caspases
• Chaperonins
• Adamantane

Topics

• Adamantane (analogs & derivatives, pharmacology)
• Animals
• Apoptosis
• Caspases (metabolism)
• Cell Cycle Proteins (metabolism)
• Cell Line
• Chaperonins (metabolism)
• Cinnamates (pharmacology)
• Fibroblasts (metabolism)
• Gene Knockdown Techniques
• Humans
• I-kappa B Kinase (genetics, metabolism)
• Inhibitor of Apoptosis Proteins (metabolism)
• Mice
• NF-kappa B (metabolism)
• NF-kappa B p52 Subunit (metabolism)
• Phosphorylation
• Protein Serine-Threonine Kinases (metabolism)
• Signal Transduction
• TNF Receptor-Associated Factor 3 (metabolism)
• Time Factors
• Transcription Factor RelB (metabolism)