title: 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.
abstract: 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.
authors: Laboratory of Molecular Oncology, Division of Pharmaceuticals, Center for Genetic Engineering and Biotechnology (CIGB), PO BOX 6162, CP10600, Havana, Cuba, yasser.perera@cigb.edu.cu.
authors: Yasser
authors: Y
authors: Perera
authors: Seidy
authors: S
authors: Pedroso
authors: Orlando
authors: O
authors: Borras-Hidalgo
authors: Dania M
authors: DM
authors: Vázquez
authors: Jamilet
authors: J
authors: Miranda
authors: Adelaida
authors: A
authors: Villareal
authors: Viviana
authors: V
authors: Falcón
authors: Luis D
authors: LD
authors: Cruz
authors: Hernán G
authors: HG
authors: Farinas
authors: Silvio E
authors: SE
authors: Perea
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D047390:Casein Kinase II / Q000037:antagonists & inhibitors / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004734:Energy Metabolism / Q000235:genetics; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D000090243:Nucleophosmin; D010456:Peptides, Cyclic / Q000008:administration & dosage; D010766:Phosphorylation / Q000187:drug effects; D012270:Ribosomes / Q000235:genetics* / Q000378:metabolism
chemical_list: D009687:Nuclear Proteins; D010456:Peptides, Cyclic; D000090243:Nucleophosmin; D047390:Casein Kinase II; C532510:CIGB-300