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


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2006-10-30

AUTHORS

Y Basaki, F Hosoi, Y Oda, A Fotovati, Y Maruyama, S Oie, M Ono, H Izumi, K Kohno, K Sakai, T Shimoyama, K Nishio, M Kuwano

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. More... »

PAGES

2736-2746

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/sj.onc.1210084

DOI

http://dx.doi.org/10.1038/sj.onc.1210084

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1003104569

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/17072343


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37 schema:description 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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44 Akt inhibitor
45 Akt pathway
46 Akt siRNA
47 CXCR4
48 DNA-binding protein family
49 E-cadherin
50 MDR1
51 MDR1 gene expression
52 N-myc downstream
53 RNA
54 S100 calcium binding protein
55 Y-box-binding protein 1
56 YB-1
57 YB-1 knockdown
58 acquisition
59 activation
60 addition
61 administration
62 animal models
63 array
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65 calcium binding protein
66 cancer
67 cancer cells
68 cells
69 characteristics
70 cold shock domain
71 cyclin B
72 cytoplasm
73 decrease
74 development
75 domain
76 downstream
77 drug resistance genes
78 environmental stimuli
79 expression
80 expression profiles
81 family
82 function
83 further development
84 gene 1
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89 human ovarian cancer cells
90 implications
91 important implications
92 inhibition
93 inhibitors
94 knockdown
95 localization
96 malignant characteristics
97 markers
98 members
99 model
100 multidrug resistance
101 novel target
102 nuclear localization
103 nuclear translocation
104 nucleus
105 oligonucleotide arrays
106 ovarian cancer
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109 pleiotropic functions
110 profile
111 protein
112 protein 1
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114 resistance
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