N-(4-hydroxyphenyl)retinamide inhibits invasion, suppresses osteoclastogenesis, and potentiates apoptosis through down-regulation of IκBα kinase and nuclear factor-κB-regulated gene products

• Published in: Cancer research (Chicago, Ill.) Ill.), 2005-10, Vol.65 (20), p.9555-9565
• Main Authors: SHISHODIA, Shishir, GUTIERREZ, Angelica M, LOTAN, Reuben, AGGARWAL, Bharat B
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Biological and medical sciences; Chemotherapy; Medical sciences; Pharmacology. Drug treatments
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-05-1585

N-(4-hydroxyphenyl) retinamide [4-HPR], a synthetic retinoid, has been shown to inhibit tumor cell growth, invasion, and metastasis by a mechanism that is not fully understood. Because the nuclear factor-κB (NF-κB) has also been shown to regulate proliferation, invasion, and metastasis of tumor cells, we postulated that 4-HPR modulates the activity of NF-κB. To test this postulate, we examined the effect of this retinoid on NF-κB and NF-κB–regulated gene products. We found that 4-HPR potentiated the apoptosis induced by tumor necrosis factor (TNF) and chemotherapeutic agents, suppressed TNF-induced invasion, and inhibited RANKL-induced osteoclastogenesis, all of which are known to require NF-κB activation. We found that 4-HPR suppressed both inducible and constitutive NF-κB activation without interfering with the direct DNA binding of NF-κB. 4-HPR was found to be synergistic with Velcade, a proteasome inhibitor. Further studies showed that 4-HPR blocked the phosphorylation and degradation of IκBα through the inhibition of activation of IκBα kinase (IKK), and this led to suppression of the phosphorylation and nuclear translocation of p65. 4-HPR also inhibited TNF-induced Akt activation linked with IKK activation. NF-κB–dependent reporter gene expression was also suppressed by 4-HPR, as was NF-κB reporter activity induced by TNFR1, TRADD, TRAF2, NIK, and IKK but not that induced by p65 transfection. The expression of NF-κB–regulated gene products involved in antiapoptosis (IAP1, Bfl-1/A1, Bcl-2, cFLIP, and TRAF1), proliferation (cyclin D1 and c-Myc), and angiogenesis (vascular endothelial growth factor, cyclooxygenase-2, and matrix metalloproteinase-9) were also down-regulated by 4-HPR. This correlated with potentiation of apoptosis induced by TNF and chemotherapeutic agents.