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- Title
Akt-dependent nuclear localization of Y-box-binding protein 1 in acquisition of malignant characteristics by human ovarian cancer cells.
- Authors
Basaki, Y.; Hosoi, F.; Oda, Y.; Fotovati, A.; Maruyama, Y.; Oie, S.; Ono, M.; Izumi, H.; Kohno, K.; Sakai, K.; Shimoyama, T.; Nishio, K.; Kuwano, M.
- 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.Oncogene (2007) 26, 2736–2746. doi:10.1038/sj.onc.1210084; published online 30 October 2006
- Subjects
OVARIAN cancer; CARRIER proteins; DNA; CANCER cells; ONCOGENES; CELLULAR pathology
- Publication
Oncogene, 2007, Vol 26, Issue 19, p2736
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/sj.onc.1210084