Sensitivity of tumor cells towards CIGB‐300 anticancer peptide relies on its nucleolar localization |
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Authors: | Yasser Perera Heydi C. Costales Yakelin Diaz Osvaldo Reyes Hernan G. Farina Lissandra Mendez Roberto E. Gómez Boris E. Acevedo Daniel E. Gomez Daniel F. Alonso Silvio E. Perea |
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Affiliation: | 1. Laboratory of Molecular Oncology, Division of Pharmaceuticals, Center for Genetic Engineering and Biotechnology (CIGB), , Havana, CP10600 Cuba;2. Peptide Synthesis Group, Chemical‐Physical Division, Center for Genetic Engineering and Biotechnology (CIGB), , Havana, CP10600 Cuba;3. Laboratory of Molecular Oncology, Quilmes National University, , Buenos Aires, Bernal, B1876BXD Argentina;4. ELEA Laboratories, , Buenos Aires, C1417 AZE Argentina |
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Abstract: | CIGB‐300 is a novel anticancer peptide that impairs the casein kinase 2‐mediated phosphorylation by direct binding to the conserved phosphoacceptor site on their substrates. Previous findings indicated that CIGB‐300 inhibits tumor cell proliferation in vitro and induces tumor growth delay in vivo in cancer animal models. Interestingly, we had previously demonstrated that the putative oncogene B23/nucleophosmin (NPM) is the major intracellular target for CIGB‐300 in a sensitive human lung cancer cell line. However, the ability of this peptide to target B23/NPM in cancer cells with differential CIGB‐300 response phenotype remained to be determined. Interestingly, in this work, we evidenced that CIGB‐300's antiproliferative activity on tumor cells strongly correlates with its nucleolar localization, the main subcellular localization of the previously identified B23/NPM target. Likewise, using CIGB‐300 equipotent doses (concentration that inhibits 50% of proliferation), we demonstrated that this peptide interacts and inhibits B23/NPM phosphorylation in different cancer cell lines as evidenced by in vivo pull‐down and metabolic labeling experiments. Moreover, such inhibition was followed by a fast apoptosis on CIGB‐300‐treated cells and also an impairment of cell cycle progression mainly after 5 h of treatment. Altogether, our data not only validates B23/NPM as a main target for CIGB‐300 in cancer cells but also provides the first experimental clues to explain their differential antiproliferative response. Importantly, our findings suggest that further improvements to this cell penetrating peptide‐based drug should entail its more efficient intracellular delivery at such subcellular localization. Copyright © 2012 European Peptide Society and John Wiley & Sons, Ltd. |
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Keywords: | CIGB‐300 CK2 B23/nucleophosmin P15‐Tat cell penetrating peptide |
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