Ribosomal RACK1 promotes chemoresistance and growth in human hepatocellular carcinoma
Ribosomal RACK1 promotes chemoresistance and growth in human hepatocellular carcinoma
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核糖体 RACK1 促进人肝细胞癌的化疗耐药性和生长
DOI：
10.1172/jci58488
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发表时间：
2012-07-01
影响因子：
15.9
通讯作者：
Gu, Jianxin
中科院分区：
文献类型：
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作者：
Ruan, Yuanyuan;Sun, Linlin;Gu, Jianxin
协调的翻译起始与细胞周期进程和细胞生长相关联，而过量的核糖体生物合成和翻译起始通常导致肿瘤转化和存活。肝细胞癌（HCC）是世界范围内最常见和最具侵袭性的癌症之一，通常对化疗药物表现出固有的高耐药性。我们发现，RACK 1，活化的C-激酶1的受体，在正常肝脏中高度表达，在肝癌中频繁上调。RACK 1的异常表达与肝癌的体外耐药和体内肿瘤生长有关。这些作用依赖于RACK 1的核糖体定位。核糖体RACK 1与PKC β II偶联，促进真核起始因子4 E（eIF 4 E）的磷酸化，从而导致参与生长和存活的有效因子的优先翻译。抑制PKC β II或耗尽eIF 4 E可在体外消除RACK 1介导的HCC化疗耐药性。我们的研究结果表明，RACK 1可能作为一个内在的因素参与肝癌的生长和生存，并建议，针对RACK 1可能是一个有效的策略，肝癌的治疗。
Coordinated translation initiation is coupled with cell cycle progression and cell growth, whereas excessive ribosome biogenesis and translation initiation often lead to tumor transformation and survival. Hepatocellular carcinoma (HCC) is among the most common and aggressive cancers worldwide and generally displays inherently high resistance to chemotherapeutic drugs. We found that RACK1, the receptor for activated C-kinase 1, was highly expressed in normal liver and frequently upregulated in HCC. Aberrant expression of RACK1 contributed to in vitro chemoresistance as well as in vivo tumor growth of HCC. These effects depended on ribosome localization of RACK1. Ribosomal RACK1 coupled with PKC beta II to promote the phosphorylation of eukaryotic initiation factor 4E (eIF4E), which led to preferential translation of the potent factors involved in growth and survival. Inhibition of PKC beta II or depletion of eIF4E abolished RACK1-mediated chemotherapy resistance of HCC in vitro. Our results imply that RACK1 may function as an internal factor involved in the growth and survival of HCC and suggest that targeting RACK1 may be an efficacious strategy for HCC treatment.