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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References
Altomare DA, Wang HQ, Skele KL, De Rienzo A, Klein-Szanto AJ, Godwin AK et al. (2004). AKT and mTOR phosphorylation is frequently detected in ovarian cancer and can be targeted to disrupt ovarian tumor cell growth. Oncogene 23: 5853–5857.
Asakuno K, Kohno K, Uchiumi T, Kubo T, Sato S, Isono M et al. (1994). Involvement of a DNA binding protein, MDR-NF1/YB-1, in human MDR1 gene expression by actinomycin D. Biochem Biophys Res Commun 199: 1428–1435.
Ashizuka M, Fukuda T, Nakamura T, Shirasuna K, Iwai K, Izumi H et al. (2002). Novel translational control through an iron-responsive element by interaction of multifunctional protein YB-1 and IRP2. Mol Cell Biol 22: 6375–6383.
Bargou RC, Jurchott K, Wagener C, Bergmann S, Metzner S, Bommert K et al. (1997). Nuclear localization and increased levels of transcription factor YB-1 in primary human breast cancers are associated with intrinsic MDR1 gene expression. Nat Med 3: 447–450.
Bennett BL, Sasaki DT, Murray BW, O’Leary EC, Sakata ST, Xu W et al. (2001). SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc Natl Acad Sci USA 98: 13681–13686.
Caruz A, Samsom M, Alonso JM, Alcami J, Baleux F, Virelizier JL et al. (1998). Genomic organization and promoter characterization of human CXCR4 gene. FEBS Lett 426: 271–278.
Cuenda A, Rouse J, Doza YN, Meier R, Cohen P, Gallagher TF et al. (1995). SB 203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin-1. FEBS Lett 364: 229–233.
Darash-Yahana M, Pikarsky E, Abramovitch R, Zeira E, Pal B, Karplus R et al. (2004). Role of high expression levels of CXCR4 in tumor growth, vascularization, and metastasis. FASEB J 18: 1240–1242.
Dooley S, Said HM, Gressner AM, Floege J, En-Nia A, Mertens PR . (2006). Y-box protein-1 is the crucial mediator of antifibrotic interferon-gamma effects. J Biol Chem 281: 1784–1795.
Eisen MB, Spellman PT, Brown PO, Botstein D . (1998). Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci USA 95: 14863–14868.
En-Nia A, Yilmaz E, Klinge U, Lovett DH, Stefanidis I, Mertens PR . (2005). Transcription factor YB-1 mediates DNA polymerase alpha gene expression. J Biol Chem 280: 702–711.
Evdokimova V, Ruzanov P, Imataka H, Raught B, Svitkin Y, Ovchinnikov LP et al. (2001). The major mRNA-associated protein YB-1 is a potent 5′ cap-dependent mRNA stabilizer. EMBO J 20: 5491–5502.
Fukuda T, Ashizuka M, Nakamura T, Shibahara K, Maeda K, Izumi H et al. (2004). Characterization of the 5′-untranslated region of YB-1 mRNA and autoregulation of translation by YB-1 protein. Nucleic Acids Res 32: 611–622.
Furukawa M, Uchiumi T, Nomoto M, Takano H, Morimoto RI, Naito S et al. (1998). The role of an inverted CCAAT element in transcriptional activation of the human DNA topoisomerase IIalpha gene by heat shock. J Biol Chem 273: 10550–10555.
Holm PS, Bergmann S, Jurchott K, Lage H, Brand K, Ladhoff A et al. (2002). YB-1 relocates to the nucleus in adenovirus-infected cells and facilitates viral replication by inducing E2 gene expression through the E2 late promoter. J Biol Chem 277: 10427–10434.
Hu L, Zaloudek C, Mills GB, Gray J, Jaffe RB . (2000). In vivo and in vitro ovarian carcinoma growth inhibition by a phosphatidylinositol 3-kinase inhibitor (LY294002). Clin Cancer Res 6: 880–886.
Huang X, Ushijima K, Komai K, Takemoto Y, Motoshima S, Kamura T et al. (2004). Co-expression of Y box-binding protein-1 and P-glycoprotein as a prognostic marker for survival in epithelial ovarian cancer. Gynecol Oncol 93: 287–291.
Ise T, Nagatani G, Imamura T, Kato K, Takano H, Nomoto M et al. (1999). Transcription factor Y-box binding protein 1 binds preferentially to cisplatin-modified DNA and interacts with proliferating cell nuclear antigen. Cancer Res 59: 342–346.
Jiang YP, Wu XH, Shi B, Wu WX, Yin GR . (2006). Expression of chemokine CXCL12 and its receptor CXCR4 in human epithelial ovarian cancer: an independent prognostic factor for tumor progression. Gynecol Oncol 103: 226–233.
Kamura T, Yahata H, Amada S, Ogawa S, Sonoda T, Kobayashi H et al. (1999). Is nuclear expression of Y box-binding protein-1 a new prognostic factor in ovarian serous adenocarcinoma? Cancer 85: 2450–2454.
Kaneko Y, Kitazato K, Basaki Y . (2004). Integrin-linked kinase regulates vascular morphogenesis induced by vascular endothelial growth factor. J Cell Sci 117: 407–415.
Kohno K, Izumi H, Uchiumi T, Ashizuka M, Kuwano M . (2003). The pleiotropic functions of the Y-box-binding protein, YB-1. Bioessays 25: 691–698.
Koike K, Uchiumi T, Ohga T, Toh S, Wada M, Kohno K et al. (1997). Nuclear translocation of the Y-box binding protein by ultraviolet irradiation. FEBS Lett 417: 390–394.
Kryczek I, Lange A, Mottram P, Alvarez X, Cheng P, Hogan M et al. (2005). CXCL12 and vascular endothelial growth factor synergistically induce neoangiogenesis in human ovarian cancers. Cancer Res 65: 465–472.
Kuwano M, Oda Y, Izumi H, Yang SJ, Uchiumi T, Iwamoto Y et al. (2004). The role of nuclear Y-box binding protein 1 as a global marker in drug resistance. Mol Cancer Ther 3: 1485–1492.
Ladomery M, Sommerville J . (1995). A role for Y-box proteins in cell proliferation. Bioessays 17: 9–11.
Maruyama Y, Ono M, Kawahara A, Yokoyama T, Basaki Y, Kage M et al. (2006). Tumor growth suppression in pancreatic cancer by a putative metastasis suppressor gene Cap43/NDRG1/Drg-1 through modulation of angiogenesis. Cancer Res 66: 6233–6242.
Matsumoto K, Wolffe AP . (1998). Gene regulation by Y-box proteins: coupling control of transcription and translation. Trends Cell Biol 8: 318–323.
Mossink MH, van Zon A, Scheper RJ, Sonneveld P, Wiemer EA . (2003). Vaults: a ribonucleoprotein particle involved in drug resistance? Oncogene 22: 7458–7467.
Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME et al. (2001). Involvement of chemokine receptors in breast cancer metastasis. Nature 410: 50–56.
Murakami T, Maki W, Cardones AR, Fang H, Tun Kyi A, Nestle FO et al. (2002). Expression of CXC chemokine receptor-4 enhances the pulmonary metastatic potential of murine B16 melanoma cells. Cancer Res 62: 7328–7334.
Ohga T, Koike K, Ono M, Makino Y, Itagaki Y, Tanimoto M et al. (1996). Role of the human Y box-binding protein YB-1 in cellular sensitivity to the DNA-damaging agents cisplatin, mitomycin C, and ultraviolet light. Cancer Res 56: 4224–4228.
Ohga T, Uchiumi T, Makino Y, Koike K, Wada M, Kuwano M et al. (1998). Direct involvement of the Y-box binding protein YB-1 in genotoxic stress-induced activation of the human multidrug resistance 1 gene. J Biol Chem 273: 5997–6000.
Porcile C, Bajetto A, Barbieri F, Barbero S, Bonavia R, Biglieri M et al. (2005). Stromal cell-derived factor-1alpha (SDF-1alpha/CXCL12) stimulates ovarian cancer cell growth through the EGF receptor transactivation. Exp Cell Res 308: 241–253.
Robledo MM, Bartolome RA, Longo N, Rodriguez-Frade JM, Mellado M, Longo I et al. (2001). Expression of functional chemokine receptors CXCR3 and CXCR4 on human melanoma cells. J Biol Chem 276: 45098–45105.
Scotton CJ, Wilson JL, Milliken D, Stamp G, Balkwill FR . (2001). Epithelial cancer cell migration: a role for chemokine receptors? Cancer Res 61: 4961–4965.
Scotton CJ, Wilson JL, Scott K, Stamp G, Wilbanks GD, Fricker S et al. (2002). Multiple actions of the chemokine CXCL12 on epithelial tumor cells in human ovarian cancer. Cancer Res 62: 5930–5938.
Sorokin AV, Selyutina AA, Skabkin MA, Guryanov SG, Nazimov IV, Richard C et al. (2005). Proteasome-mediated cleavage of the Y-box-binding protein 1 is linked to DNA-damage stress response. EMBO J 24: 3602–3612.
Stein U, Bergmann S, Scheffer GL, Scheper RJ, Royer HD, Schlag PM et al. (2005). YB-1 facilitates basal and 5-fluorouracil-inducible expression of the human major vault protein (MVP) gene. Oncogene 24: 3606–3618.
Stein U, Jurchott K, Walther W, Bergmann S, Schlag PM, Royer HD . (2001). Hyperthermia-induced nuclear translocation of transcription factor YB-1 leads to enhanced expression of multidrug resistance-related ABC transporters. J Biol Chem 276: 28562–28569.
Stenina OI, Poptic EJ, DiCorleto PE . (2000). Thrombin activates a Y box-binding protein (DNA-binding protein B) in endothelial cells. J Clin Invest 106: 579–587.
Sutherland BW, Kucab J, Wu J, Lee C, Cheang MC, Yorida E et al. (2005). Akt phosphorylates the Y-box binding protein 1 at Ser102 located in the cold shock domain and affects the anchorage-independent growth of breast cancer cells. Oncogene 24: 4281–4292.
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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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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DOI: https://doi.org/10.1038/sj.onc.1210084
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