MYC phosphorylation, activation, and tumorigenic potential in hepatocellular carcinoma are regulated by HMG-CoA reductase.
MYC phosphorylation, activation, and tumorigenic potential in hepatocellular carcinoma are regulated by HMG-CoA reductase.
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DOI：
10.1158/0008-5472.can-10-3367
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发表时间：
2011-03-15
期刊：
影响因子：
11.2
通讯作者：
Felsher DW
中科院分区：
文献类型：
--
作者：
Cao Z;Fan-Minogue H;Bellovin DI;Yevtodiyenko A;Arzeno J;Yang Q;Gambhir SS;Felsher DW
MYC是许多癌症的潜在靶点，但不适用于现有的药理学方法。他汀类药物对HMG-CoA还原酶的抑制作用已显示出对许多癌症的潜在疗效。在这里，我们证明了阿托伐他汀抑制HMG-CoA还原酶阻断MYC磷酸化和活化，抑制体内MYC诱导的HCC转基因模型以及人HCC衍生细胞系中的肿瘤起始和生长。为了证实特异性，我们发现阿托伐他汀的抗肿瘤作用被HMG-CoA还原酶产物甲羟戊酸的共同治疗阻断。此外，通过使用一种新的分子成像传感器，我们证实HMG-CoA还原酶的抑制阻断MYC在体内的磷酸化。重要的是，将MYC在Ser 62或Thr 58处的磷酸化突变体引入肿瘤阻断了它们对HMG-CoA还原酶抑制的敏感性。最后，我们证明HMG-CoA还原酶的抑制通过Rac GT3抑制MYC磷酸化。因此，HMG-CoA还原酶是MYC磷酸化、活化和致瘤特性的关键调节剂。HMG-CoA还原酶的抑制可能是治疗MYC相关HCC以及其他肿瘤的有用靶点。
MYC is a potential target for many cancers but is not amenable to existing pharmacological approaches. Inhibition of HMG-CoA reductase by statins has shown potential efficacy against a number of cancers. Here, we demonstrate that inhibition of HMG-CoA reductase by atorvastatin blocks both MYC phosphorylation and activation, suppressing tumor initiation and growth in vivo in a transgenic model of MYC-induced HCC as well as in human HCC-derived cell lines. To confirm specificity, we show that the anti-tumor effects of atorvastatin are blocked by co-treatment with the HMG-CoA reductase product, Mevalonate. Moreover, by using a novel molecular imaging sensor, we confirm that inhibition of HMG-CoA reductase blocks MYC phosphorylation in vivo. Importantly, the introduction of phosphorylation mutants of MYC at Ser62 or Thr58 into tumors blocks their sensitivity to inhibition of HMG-CoA reductase. Finally, we demonstrate that inhibition of HMG-CoA reductase suppresses MYC phosphorylation through Rac GTPase. Therefore, HMG-CoA reductase is a critical regulator of MYC phosphorylation, activation, and tumorigenic properties. The inhibition of HMG-CoA reductase may be a useful target for the treatment of MYC-associated HCC as well as other tumors.