Synergistic growth inhibition by acyclic retinoid and vitamin K2 in human hepatocellular carcinoma cells
Synergistic growth inhibition by acyclic retinoid and vitamin K2 in human hepatocellular carcinoma cells
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DOI：
10.1111/j.1349-7006.2006.00384.x
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发表时间：
2007-03-01
期刊：
影响因子：
5.7
通讯作者：
Moriwaki, Hisataka
中科院分区：
文献类型：
--
作者：
Kanamori, Toh;Shimizu, Masahito;Moriwaki, Hisataka
肝细胞癌（HCC）是世界范围内最常见的癌症之一。然而，有效的化学预防和化疗药物，这种癌症尚未开发。在临床试验中，无环类维生素A（ACR）和维生素K-2（VK 2）降低了HCC的复发率。在本研究中，我们研究了ACR或另一种维甲酸9-顺式维甲酸（9 cRA）加VK 2在HuH 7人肝癌细胞系中的可能联合作用。我们发现，1.0 μ M ACR或1.0 μ M 9 cRA加10 μ M VK 2的组合协同抑制HuH 7细胞的生长，而不影响Hc正常人肝细胞的生长。ACR与VK 2的联合处理也协同作用以诱导HuH 7细胞的凋亡。单独使用VK 2治疗通过抑制Ras活化和细胞外信号调节激酶磷酸化来抑制类维生素A X受体（RXR）α蛋白的磷酸化，该蛋白被认为是肝癌发生的关键因素。此外，当细胞与ACR共处理时，VK 2对RXR α磷酸化的抑制增强。类维生素A加VK 2的组合显著增加HuH 7细胞中的视黄酸受体响应元件和类维生素A X受体响应元件启动子活性。我们的研究结果表明，类维生素A（特别是ACR）和VK 2协同抑制Ras/MAPK信号通路的激活，随后抑制RXR α的磷酸化和肝癌细胞的生长。因此，这种组合可能是有效的化学预防和化疗的肝癌。
Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide. However, effective chemopreventive and chemotherapeutic agents for this cancer have not yet been developed. In clinical trials acyclic retinoid (ACR) and vitamin K-2 (VK2) decreased the recurrence rate of HCC. In the present study we examined the possible combined effects of ACR or another retinoid 9-cis retinoic acid (9cRA) plus VK2 in the HuH7 human HCC cell line. We found that the combination of 1.0 mu M ACR or 1.0 mu M 9cRA plus 10 mu M VK2 synergistically inhibited the growth of HuH7 cells without affecting the growth of Hc normal human hepatocytes. The combined treatment with ACR plus VK2 also acted synergistically to induce apoptosis in HuH7 cells. Treatment with VK2 alone inhibited phosphorylation of the retinoid X receptor (RXR)alpha protein, which is regarded as a critical factor for liver carcinogenesis, through inhibition of Ras activation and extracellular signal-regulated kinase phosphorylation. Moreover, the inhibition of RXR alpha phosphorylation by VK2 was enhanced when the cells were cotreated with ACR. The combination of retinoids plus VK2 markedly increased both the retinoic acid receptor responsive element and retinoid X receptor responsive element promoter activities in HuH7 cells. Our results suggest that retinoids (especially ACR) and VK2 cooperatively inhibit activation of the Ras/MAPK signaling pathway, subsequently inhibiting the phosphorylation of RXR alpha and the growth of HCC cells. This combination might therefore be effective for the chemoprevention and chemotherapy of HCC.