Pharmacologic inhibition of the CK2-mediated phosphorylation of B23/NPM in cancer cells selectively modulates genes related to protein synthesis, energetic metabolism, and ribosomal biogenesis

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• 作者：Yasser Perera ; Seidy Pedroso ; Orlando Borras-Hidalgo…
• 关键词：B23/NPM ; CK2 inhibitor ; CIGB ; 300 ; Nucleophosmin phosphorylation
• 刊名：Molecular and Cellular Biochemistry
• 出版年：2015
• 出版时间：June 2015
• 年：2015
• 卷：404
• 期：1-2
• 页码：103-112
• 全文大小：2,219 KB
• 参考文献：1.Grisendi S, Mecucci C, Falini B, Pandolfi PP (2006) Nucleophosmin and cancer. Nat Rev Cancer 6:493-05View Article PubMed
  2.Borer RA, Lehner CF, Eppenberger HM, Nigg EA (1989) Major nucleolar proteins shuttle between nucleus and cytoplasm. Cell 56:379-90View Article PubMed
  3.Yun JP, Chew EC, Liew CT, Chan JY, Jin ML, Ding MX, Fai YH, Li HK, Liang XM, Wu QL (2003) Nucleophosmin/B23 is a proliferate shuttle protein associated with nuclear matrix. J Cell Biochem 90:1140-148View Article PubMed
  4.Hingorani K, Szebeni A, Olson MOJ (2000) Mapping the functional domains of nucleolar protein B23. J Biol Chem 275:24451-4457View Article PubMed
  5.Murano TK, Okuwaki M, Hisaoka M, Nagata K (2008) Transcription regulation of the rRNA gene by a multifunctional nucleolar protein, B23/nucleophosmin, through its histone chaperone activity. Mol Cell Biol 28:3114-126View Article PubMed Central PubMed
  6.Wu MH, Yung BYM (2002) UV Stimulation of nucleophosmin/B23 expression is an immediate-early gene response induced by damaged DNA. J Biol Chem 277:48234-8240View Article PubMed
  7.Li J, Zhang X, Sejas DP, Bagby GC, Pang Q (2004) Hypoxia-induced nucleophosmin protects cell death through inhibition of p53. J Biol Chem 279:41275-1279View Article PubMed
  8.Zhang H, Shi X, Paddon H, Hampong M, Dai W, Pelech S (2004) B23/nucleophosmin serine 4 phosphorylation mediates mitotic functions of polo-like kinase 1. J Biol Chem 279:35726-5734View Article PubMed
  9.Takemura M, Sato K, Nishio M, Akiyama T, Umekawa H, Yoshida S (1999) Nucleolar protein B23.1 binds to retinoblastoma protein and synergistically stimulates DNA polymerase alpha activity. J Biochem 125:904-09View Article PubMed
  10.Dhar SK, Lynn BC, Daosukho C, St. Clair DK (2004) Identification of nucleophosmin as an NF-κB co-activator for the induction of the human SOD2 gene. J Biol Chem 279:28209-8219View Article PubMed Central PubMed
  11.Okuwaki M (2008) The structure and functions of NPM1/nucleophsmin/B23, a multifunctional nucleolar acidic protein. J Biochem 222:1-
  12.Okuda M, Horn HF, Tarapore P, Tokuyama Y, Smulian AG, Chan PK, Knudsen ES, Hofmann IA, Snyder JD, Bove KE, Fukasawa K (2000) Nucleophosmin/B23 is a target of CDK2/cyclin E in centrosome duplication. Cell 103:127-40View Article PubMed
  13.Okuwaki M, Tsujimoto M, Nagata K (2002) The RNA binding activity of a ribosome biogenesis factor, nucleophosmin/B23, is modulated by phosphorylation with a cell cycle-dependent kinase and by association with its subtype. Mol Biol Cell 13:2016-030View Article PubMed Central PubMed
  14.Chan PK, Liu QR, Durban E (1990) The major phosphorylation site of nucleophosmin (B23) is phosphorylated by a nuclear kinase II. Biochem J 270:549-52PubMed Central PubMed
  15.Jiang PS, Chang JH, Yung YB (2000) Different kinases phosphorylate nucleophosmin/B23 at different sites during G(2) and M phases of the cell cycle. Cancer Lett 153:151-60View Article PubMed
  16.Negi S, Olson MO (2006) Effects of interphase and mitotic phosphorylation on the mobility and location of nucleolar protein B23. J Cell Sci 401:616-20
  17.Louvet E, Junera HR, Berthuy I, Hernandez-Verdun D (2006) Compartmentation of the nucleolar processing proteins in the granular component is a CK2-driven process. Mol Biol Cell 17:2537-546View Article PubMed Central PubMed
  18.Cozza G, Pinna LA, Moro S (2013) Kinase CK2 inhibition: an update. Curr Med Chem 20:671-93View Article PubMed
  19.Perea SE, Reyes O, Puchades Y, Mendoza O, Vispo NS, Torrens I, Santos A, Silva R, Acevedo B, López E, Falcón V, Alonso DF (2004) Antitumor effect of a novel proapoptotic peptide that impairs the fosforilación by the protein kinase 2 (casein kinase 2). Cancer Res 64:7127-129View Article PubMed
  20.Perera Y, Farina HG, Gil J, Rodriguez A, Benavent F, Castellanos L, Gómez RE, Acevedo BE, Alonso DF, Perea SE (2009) Anticancer peptide CIGB-300 binds to nucleophosmin/B23, impairs its CK2-mediated phosphorylation, and leads to apoptosis through its nucleolar disassembly activity. Mol Cancer Ther 8:1189-196View Article PubMed
  21.Perera Y, Costales HC, Diaz Y, Reyes O, Farina HG, Mendez L, Gómez RE, Acevedo BE, Gomez DE, Alonso DF, Perea SE (2012) Sensitivity of tumor cells towards CIGB-300 anticancer peptide relies on its nucleolar localization. J Pept Sci 18:215-23View Article PubMed
  22.Diatchenko L, Lau YF, Campbell AP, Chenchik A, Moqadam F, Huang B, Lukyanov S, Lukyanov K, Gurskaya N, Sverdlov ED, Siebert PD (1996) Suppression subtractive hybridization: a method for generating differentially regulated or tissue-specific cDNA probes and libraries. Proc Natl Acad Sci 93:6025-030View Article PubMed Central PubMed
  23.Huang DW, Sherman BT, Lempicki RA (2009) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4:44-7View Article
  24.Rodriguez-Ulloa A, Ramos Y, Gil J, Perera Y, Castellanos-Serra L, Garcia Y, Betanco
• 作者单位：Yasser Perera (1)
  Seidy Pedroso (2)
  Orlando Borras-Hidalgo (3)
  Dania M. Vázquez (2)
  Jamilet Miranda (4)
  Adelaida Villareal (2)
  Viviana Falcón (5)
  Luis D. Cruz (6)
  Hernán G. Farinas (7)
  Silvio E. Perea (1)
  
  1. Laboratory of Molecular Oncology, Division of Pharmaceuticals, Center for Genetic Engineering and Biotechnology (CIGB), PO BOX 6162, CP10600, Havana, Cuba
  2. Department of Genomics, Center for Genetic Engineering and Biotechnology (CIGB), Havana, Cuba
  3. Plant Division, Center for Genetic Engineering and Biotechnology (CIGB), Havana, Cuba
  4. Bioinformatics Department, Center for Genetic Engineering and Biotechnology (CIGB), Havana, Cuba
  5. Chemical-Physical Division, Center for Genetic Engineering and Biotechnology (CIGB), Havana, Cuba
  6. Center for Advanced Studies of Cuba (CEAC), Carretera San Antonio, km 1-1/2, Puentes Grandes, Havana, Cuba
  7. Laboratory of Molecular Oncology, Quilmes National University, R. Sáenz Pe?a 352, Bernal B1876BXD, Buenos Aires, Argentina
  
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Life Sciences
  Biochemistry
  Medical Biochemistry
  Oncology
  Cardiology
  
• 出版者：Springer Netherlands
• ISSN：1573-4919

文摘

B23/NPM is a multifunctional nucleolar protein frequently overexpressed, mutated, or rearranged in neoplastic tissues. B23/NPM is involved in diverse biological processes and is mainly regulated by heteroligomer association and posttranslational modification, phosphorylation being a major posttranslational event. While the role of B23/NPM in supporting and/or driving malignant transformation is widely recognized, the particular relevance of its CK2-mediated phosphorylation remains unsolved. Interestingly, the pharmacologic inhibition of such phosphorylation event by CIGB-300, a clinical-grade peptide drug, was previously associated to apoptosis induction in tumor cell lines. In this work, we sought to identify the biological processes modulated by CIGB-300 in a lung cancer cell line using subtractive suppression hybridization and subsequent functional annotation clustering. Our results indicate that CIGB-300 modulates a subset of genes involved in protein synthesis (ES?=?8.4, p?<?0.001), mitochondrial ATP metabolism (ES?=?2.5, p?<?0.001), and ribosomal biogenesis (ES?=?1.5, p?<?0.05). The impairment of these cellular processes by CIGB-300 was corroborated at the molecular and cellular levels by Western blot (P-S6/P-4EBP1, translation), confocal microscopy (JC-1, mitochondrial potential), qPCR (45SrRNA/p21, ribosome biogenesis), and electron microscopy (nucleolar structure, ribosome biogenesis). Altogether, our findings provide new insights on the potential relevance of the CK2-mediated phosphorylation of B23/NPM in cancer cells, revealing at the same time the potentialities of its pharmacological manipulation for cancer therapy. Finally, this work also suggests several candidate gene biomarkers to be evaluated during the clinical development of the anti-CK2 peptide CIGB-300.