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

Ribosomal RACK1 promotes chemoresistance and growth in human hepatocellular carcinoma

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 4

Ribosomal RACK1 enhances global translation and the phosphorylation of eIF4E in a PKCβII-dependent manner.

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Ribosomal RACK1 enhances global translation and the phosphorylation of e...
(A) Ribosomal RACK1 promotes de novo protein synthesis. The rate of [35S]-methionine (35S-Met) incorporation was assessed relative to that of cells transfected with empty vector. (B) RACK1 is required for efficient translation. (C) RACK1 stimulates translation requiring PKCβII activity. Transfected Huh7 cells were incubated with CGP53353 (5 μM) or LY333531 (50 nM) for 1 hour. (D) Functional association with PKCβII is required for RACK1-stimulated translation. Intracellular delivery of TAT peptides was conducted as described in the Methods. (E) Ribosomal RACK1 enriches PKCβII with poly(A) mRNA. Huh7 cells were transfected as indicated, followed by oligo-dT pull-down assay. (F) The effect of ribosomal RACK1 on the phosphorylation of eIF2α and eIF4E. (G) PKCβII activity is required for RACK1-mediated phosphorylation of eIF4E. Huh7 cells were transfected and treated as in C. (H) RACK1/PKCβII interaction is required for RACK1-mediated phosphorylation of eIF4E. Huh7 cells were transfected and treated as in D. In A–D, assays were performed in quadruplicate (n = 4). In E–H, numbers represent relative expression of PKCβII, p-eIF2α (S51), or p-eIF4E (S209), which was quantified by comparing with GAPDH.