Molecular mechanism for growth suppression of human hepatocellular carcinoma cells by acyclic retinoid
Molecular mechanism for growth suppression of human hepatocellular carcinoma cells by acyclic retinoid
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DOI：
10.1093/carcin/bgg090
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发表时间：
2003-08-01
期刊：
影响因子：
4.7
通讯作者：
Moriwaki, H
中科院分区：
文献类型：
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作者：
Matsushima-Nishiwaki, R;Okuno, M;Moriwaki, H
我们以前已经报道，非环维A酸类化合物是一种合成的维甲酸X受体α(RXRpha)配体，可以抑制慢性肝病患者肝细胞癌(HCC)的发展。另一方面，由于细胞外信号调节激酶(ERK)1/2介导的RXRα的磷酸化和RXRα的失活，肝癌细胞对天然的RXRα配体-9-顺式维甲酸(9cRA)的生理浓度变得不耐受。在这里，我们证明了非环类维甲酸通过失活Ras-Erk 1/2信号系统，从而使RXRpha去磷酸化，恢复了人肝癌来源的Huh7细胞中RXRpha的功能。相反，9cRA不能抑制磷酸化Erk 1/2水平和随后的RXRpha磷酸化。虽然9cRA也抑制RAS活性，但它同时下调丝裂原活化蛋白激酶磷酸酶-1，这是一种使ERK失活的酶，从而使ERK的磷酸化状态保持不变。9cRA(一种有效的配体)和去环维A酸(一种防止磷酸化的弱配体)的组合在通过RXR反应元件反式激活和抑制Huh7细胞的增殖方面产生了显着的协同作用。这些事件为去环维A酸类化合物抗肝癌活性提供了新的分子基础。
We have reported previously that acyclic retinoid, a synthetic retinoid X receptor alpha (RXRalpha)-ligand, suppresses the development of hepatocellular carcinoma (HCC) in patients with chronic liver disease. On the other hand, HCCs become refractory to physiological concentrations of the natural RXRalpha-ligand, 9-cis retinoic acid (9cRA), due to extracellular signal-regulated kinase (Erk) 1/2-mediated phosphorylation and inactivation of RXRalpha. Here, we show that acyclic retinoid restores the function of RXRalpha in human HCC-derived HuH7 cells by inactivating the Ras-Erk 1/2 signaling system, thereby dephosphorylating RXRalpha. In contrast, 9cRA failed to suppress phosphoErk 1/2 levels and subsequent RXRalpha phosphorylation. Although 9cRA also suppressed Ras activity, it simultaneously down-regulated mitogen-activated protein kinase phosphatase-1, an enzyme that inactivates Erk, thereby leaving the phosphorylation status of Erk unchanged. A combination of 9cRA (a potent ligand) and acyclic retinoid (a weak ligand preventing phosphorylation) resulted in a marked cooperation in transactivation via the RXR-response element and in inhibiting the proliferation of HuH7 cells. These events provide a novel molecular basis for the antitumor activity of acyclic retinoid against HCC.