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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.
Cancer Res. 2005 Oct 15; 65(20):9555-65.CR

Abstract

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.

Authors+Show Affiliations

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.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

16230421

Citation

Shishodia, Shishir, et al. "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." Cancer Research, vol. 65, no. 20, 2005, pp. 9555-65.
Shishodia S, Gutierrez AM, Lotan R, et al. 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. Cancer Res. 2005;65(20):9555-65.
Shishodia, S., Gutierrez, A. M., Lotan, R., & Aggarwal, B. B. (2005). 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. Cancer Research, 65(20), 9555-65.
Shishodia S, et al. 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. Cancer Res. 2005 Oct 15;65(20):9555-65. PubMed PMID: 16230421.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Shishodia,Shishir, AU - Gutierrez,Angelica M, AU - Lotan,Reuben, AU - Aggarwal,Bharat B, PY - 2005/10/19/pubmed PY - 2005/12/20/medline PY - 2005/10/19/entrez SP - 9555 EP - 65 JF - Cancer research JO - Cancer Res VL - 65 IS - 20 N2 - 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. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/16230421/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_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=16230421 DB - PRIME DP - Unbound Medicine ER -