Tatebe Hideharu, Shimizu Masahito, Shirakami Yohei, Tsurumi Hisashi, Moriwaki Hisataka
Department of Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
Clin Cancer Res. 2008 May 1;14(9):2806-12. doi: 10.1158/1078-0432.CCR-07-4708.
A malfunction of retinoid X receptor-alpha (RXRalpha) due to phosphorylation by the Ras/mitogen-activated protein kinase signaling pathway is associated with the development of hepatocellular carcinoma (HCC). The humanized anti-HER2 monoclonal antibody trastuzumab inhibits the activation of HER2 and its multiple downstream signaling pathways, including the Ras/mitogen-activated protein kinase pathway. In this study, the effects of phosphorylation of RXRalpha on the ability of RXRalpha ligand 9-cis-retinoic acid (9cRA) and trastuzumab to inhibit growth of HCC cells was examined.
The effects of a combination of 9cRA plus trastuzumab on the inhibition of cell growth in HLF human HCC cells which express constitutive activation of HER2 protein were examined.
The combination of 9cRA plus trastuzumab synergistically inhibited the growth of HLF cells without affecting the growth of Hc normal human hepatocytes. Combined treatment with these agents acted synergistically to induce apoptosis in HLF cells. The treatment of HLF cells with trastuzumab alone inhibited the phosphorylation of HER2, RXRalpha, ERK, Akt, and Stat3 proteins and these effects were enhanced when the cells were cotreated with 9cRA. Reporter assays indicated that the combination of 9cRA plus trastuzumab markedly increased both the retinoic acid responsive element and retinoid X responsive element promoter activities in HLF cells.
9cRA and trastuzumab cooperatively inhibit the activation of HER2 and its downstream signaling pathways, subsequently inhibiting the phosphorylation of RXRalpha and the growth of HCC cells. This combination might therefore be effective for the chemoprevention and chemotherapy of HCC.
维甲酸X受体α（RXRα）因Ras/丝裂原活化蛋白激酶信号通路磷酸化而发生的功能障碍与肝细胞癌（HCC）的发生发展相关。人源化抗HER2单克隆抗体曲妥珠单抗可抑制HER2及其多个下游信号通路的激活，包括Ras/丝裂原活化蛋白激酶通路。在本研究中，检测了RXRα磷酸化对RXRα配体9-顺式视黄酸（9cRA）和曲妥珠单抗抑制HCC细胞生长能力的影响。
检测9cRA联合曲妥珠单抗对表达组成型活化HER2蛋白的HLF人HCC细胞生长抑制的影响。
9cRA联合曲妥珠单抗协同抑制HLF细胞生长，而不影响Hc正常人肝细胞的生长。这些药物联合治疗协同诱导HLF细胞凋亡。单独用曲妥珠单抗处理HLF细胞可抑制HER2、RXRα、ERK、Akt和Stat3蛋白的磷酸化，当细胞与9cRA联合处理时，这些作用增强。报告基因检测表明，9cRA联合曲妥珠单抗显著增加了HLF细胞中视黄酸反应元件和维甲酸X反应元件启动子的活性。
9cRA和曲妥珠单抗协同抑制HER2及其下游信号通路的激活，随后抑制RXRα的磷酸化和HCC细胞的生长。因此，这种联合用药可能对HCC的化学预防和化疗有效。
