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Akt-dependent nuclear localization of Y-box-binding protein 1 in acquisition of malignant characteristics by human ovarian cancer cells

Abstract

Y-box-binding protein 1 (YB-1), which is a member of the DNA-binding protein family containing a cold-shock domain, has pleiotropic functions in response to various environmental stimuli. As we previously showed that YB-1 is a global marker of multidrug resistance in ovarian cancer and other tumor types. To identify YB-1-regulated genes in ovarian cancers, we investigated the expression profile of YB-1 small-interfering RNA (siRNA)-transfected ovarian cancer cells using a high-density oligonucleotide array. YB-1 knockdown by siRNA upregulated 344 genes, including MDR1, thymidylate synthetase, S100 calcium binding protein and cyclin B, and downregulated 534 genes, including CXCR4, N-myc downstream regulated gene 1, E-cadherin and phospholipase C. Exogenous serum addition stimulated YB-1 translocation from the cytoplasm to the nucleus, and treatment with Akt inhibitors as well as Akt siRNA and integrin-linked kinase (ILK) siRNA specifically blocked YB-1 nuclear localization. Inhibition of Akt activation downregulated CXCR4 and upregulated MDR1 (ABCB1) gene expression. Administration of Akt inhibitor resulted in decrease in nuclear YB-1-positive cancer cells in a xenograft animal model. Akt activation thus regulates the nuclear translocation of YB-1, affecting the expression of drug-resistance genes and other genes associated with the malignant characteristics in ovarian cancer cells. Therefore, the Akt pathway could be a novel target of disrupting the nuclear translocation of YB-1 that has important implications for further development of therapeutic strategy against ovarian cancers.

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Acknowledgements

We thank Y Yamada and Y Yamasaki in Hanno Research Center of Taiho Pharmaceutical Co. Ltd. for fruitful discussion, and N Shinbaru in Kyushu University for editorial help. This study was supported by the COE program for Medical Sciences, Kurume University, and grant-in-aid for scientific research on priority areas cancer from Ministry of Education Culture, Sports Science, and Technology of Japan and the 2nd-Comprehensive Ten-Year Strategy for Cancer Control from the Ministry of Health, Welfare and Labor, Japan.

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Correspondence to Y Basaki.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Basaki, Y., Hosoi, F., Oda, Y. et al. Akt-dependent nuclear localization of Y-box-binding protein 1 in acquisition of malignant characteristics by human ovarian cancer cells. Oncogene 26, 2736–2746 (2007). https://doi.org/10.1038/sj.onc.1210084

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