INVESTIGADORES
ALONSO Daniel Fernando
artículos
Título:
Anticancer peptide CIGB-300 binds to nucleophosmin/B23, impairs its CK2-mediated phosphorylation, and leads to apoptosis through its nucleolar disassembly activity
Autor/es:
Y PERERA; HG FARINA; J GIL; A RODRIGUEZ; F BENAVENT ACERO; L CASTELLANOS; RE GOMEZ; BE ACEVEDO; DF ALONSO; SE PEREA
Revista:
MOLECULAR CANCER THERAPEUTICS
Editorial:
AMER ASSOC CANCER RESEARCH
Referencias:
Año: 2009 vol. 8 p. 1189 - 1196
ISSN:
1535-7163
Resumen:
CIGB-300, formerly known as P15-tat, is a proapoptotic peptide with
established antiproliferative activity in vitro and antitumoral activity
in vivo. This hypothesis-driven peptide was initially selected for its
ability to impair the in vitro CK2-mediated phosphorylation in one of
its substrates through direct binding to the conserved acidic
phosphoaceptor domain. However, the actual in vivo target(s) on human
cancer cells among the hundreds of CK2 substrates as well as the
subsequent events that lead to apoptosis on tumor cells remains to be
determined. In this work, we identified the multifunctional oncoprotein
nucleophosmin/B23 as a major target for CIGB-300. In vivo, the
CIGB-300-B23 interaction was shown by pull-down experiments and
confirmed by the early in situ colocalization of both molecules in the
cell nucleolus. Moreover, CIGB-300 inhibits the CK2-mediated
phosphorylation of B23 in a dose-dependent fashion both in vitro and in
vivo as shown using the recombinant GST fusion protein and the metabolic
labeling approach, respectively. Such phosphorylation impairment was
correlated with the ability of CIGB-300 to induce nucleolar disassembly
as documented by the use of established markers for nucleolar structure.
Finally, we showed that such a sequence of events leads to the rapid
and massive onset of apoptosis both at the molecular and cellular
levels. Collectively, these findings provide important clues by which
the CIGB-300 peptide exerts its proapoptotic effect on tumor cells and
highlights the suitability of the B23/CK2 pathway for cancer-targeted
therapy.