N-(4-hydroxyphenyl)retinamide inhibits invasion, suppresses osteoclastogenesis, and potentiates apoptosis through down-regulation of I(kappa)B(alpha) kinase and nuclear factor-kappaB-regulated gene products.
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-kappaB (NF-kappaB) has also been shown to regulate proliferation, invasion, and metastasis of tumor cells, we postulated that 4-HPR modulates the activity of NF-kappaB. To test this postulate, we examined the effect of this retinoid on NF-kappaB and NF-kappaB-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-kappaB activation. We found that 4-HPR suppressed both inducible and constitutive NF-kappaB activation without interfering with the direct DNA binding of NF-kappaB. 4-HPR was found to be synergistic with Velcade, a proteasome inhibitor. Further studies showed that 4-HPR blocked the phosphorylation and degradation of IkappaBalpha through the inhibition of activation of IkappaBalpha 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-kappaB-dependent reporter gene expression was also suppressed by 4-HPR, as was NF-kappaB reporter activity induced by TNFR1, TRADD, TRAF2, NIK, and IKK but not that induced by p65 transfection. The expression of NF-kappaB-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.
Shishodia
Shishir
S
Cytokine Research Laboratory, Department of Experimental Therapeutics and Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Gutierrez
Angelica M
AM
Lotan
Reuben
R
Aggarwal
Bharat B
BB
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D018288:Carcinoma, Small Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors; D048708:Cell Growth Processes / Q000187:drug effects; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D017313:Fenretinide / Q000494:pharmacology*; D016259:Genes, myc / Q000187:drug effects; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D020672:I-kappa B Proteins / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics; D011719:Pyrazines / Q000494:pharmacology; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics
D000970:Antineoplastic Agents; D001897:Boronic Acids; D002352:Carrier Proteins; D020672:I-kappa B Proteins; C489427:MYC protein, human; D008562:Membrane Glycoproteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D016271:Proto-Oncogene Proteins c-myc; D011719:Pyrazines; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D019938:Cyclin D1; D000072000:NF-KappaB Inhibitor alpha; D017313:Fenretinide; D000069286:Bortezomib; D051546:Cyclooxygenase 2; D051058:Oncogene Protein v-akt; D051550:I-kappa B Kinase