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Ribosomal RACK1 promotes chemoresistance and growth in human hepatocellular carcinoma
Yuanyuan Ruan, … , Aiguo Shen, Jianxin Gu
Yuanyuan Ruan, … , Aiguo Shen, Jianxin Gu
Published June 1, 2012
Citation Information: J Clin Invest. 2012;122(7):2554-2566. https://doi.org/10.1172/JCI58488.
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Research Article Oncology Article has an altmetric score of 12

Ribosomal RACK1 promotes chemoresistance and growth in human hepatocellular carcinoma

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Abstract

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 PKCβII 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 PKCβII 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.

Authors

Yuanyuan Ruan, Linlin Sun, Yuqing Hao, Lijing Wang, Jiejie Xu, Wen Zhang, Jianhui Xie, Liang Guo, Lei Zhou, Xiaojing Yun, Hongguang Zhu, Aiguo Shen, Jianxin Gu

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Figure 2

Ribosomal RACK1 contributes to the chemotherapy resistance of HCC in vitro.

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Ribosomal RACK1 contributes to the chemotherapy resistance of HCC in vit...
(A) Overexpression of RACK1 enhances the doxorubicin (Dox) resistance of HCC cell lines. Twenty-four hours after transfection with vector or wild-type RACK1, HepG2 (100 μg/ml), Huh7 (20 μg/ml), and Hep3B (50 μg/ml) cells were treated with doxorubicin for indicated times. Cellular apoptosis was determined by annexin V staining. (B) Depletion of RACK1 sensitizes HCC cells to doxorubicin-induced apoptosis. Seventy-two hours after transfection with shLuc or shRACK1, cells were treated with doxorubicin for another 24 hours as in A. Numbers represent relative expression of RACK1, which was quantified by comparing it with GAPDH. (C) The ribosome localization of RACK1 is required for doxorubicin resistance of HCC. Twenty-four hours after transfection, Huh7 cells were treated with doxorubicin (20 μg/ml) for another 24 hours. (D) The DE mutant sensitizes Huh7 cells to doxorubicin-induced apoptosis. Huh7 cells were transiently transfected with increasing doses of wild-type RACK1 or the DE mutant and treated as in C. (E) Wild-type RACK1, but not the DE mutant, restores the chemoresistance of RACK1-depleted HCC cells. HCC cells expressing shRACK1 were supertransfected with the constructs as indicated and treated with doxorubicin as in A for 24 hours. All assays were performed in triplicate.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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