Shishodia Shishir, Gutierrez Angelica M, Lotan Reuben, Aggarwal Bharat B
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.
Cancer Res. 2005 Oct 15;65(20):9555-65. 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-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.
N-(4-羟基苯基)视黄酸[4-HPR]，一种合成类视黄醇，已被证明可通过一种尚未完全了解的机制抑制肿瘤细胞的生长、侵袭和转移。由于核因子-κB（NF-κB）也已被证明可调节肿瘤细胞的增殖、侵袭和转移，我们推测4-HPR可调节NF-κB的活性。为了验证这一推测，我们研究了这种类视黄醇对NF-κB及NF-κB调节的基因产物的影响。我们发现4-HPR增强了肿瘤坏死因子（TNF）和化疗药物诱导的细胞凋亡，抑制了TNF诱导的侵袭，并抑制了RANKL诱导的破骨细胞生成，所有这些都已知需要NF-κB激活。我们发现4-HPR抑制了诱导型和组成型NF-κB激活，而不干扰NF-κB与DNA的直接结合。发现4-HPR与蛋白酶体抑制剂万珂具有协同作用。进一步研究表明，4-HPR通过抑制IκBα激酶（IKK）的激活来阻断IκBα的磷酸化和降解，这导致p65的磷酸化和核转位受到抑制。4-HPR还抑制了与IKK激活相关的TNF诱导的Akt激活。4-HPR也抑制了NF-κB依赖的报告基因表达，以及由TNFR1、TRADD、TRAF2、NIK和IKK诱导的NF-κB报告活性，但不抑制由p65转染诱导的活性。参与抗凋亡（IAP1、Bfl-1/A1、Bcl-2、cFLIP和TRAF1）、增殖（细胞周期蛋白D1和c-Myc）和血管生成（血管内皮生长因子、环氧化酶-2和基质金属蛋白酶-9）的NF-κB调节基因产物的表达也被4-HPR下调。这与TNF和化疗药物诱导的细胞凋亡增强相关。
