INHIBITION OF PROLINE-DIRECTED PHOSPHORYLATION SIGNALING AS A POTENTIAL ANTITUMOR STRATEGY

DI BENEDETTO, CAROLINA; PAOLETTI, LUCIANA; BANCHIO, C; GIRARDINI, J

Rosario

Congreso; Reunoón anual de la Sociedad Argentina de Bioquímica y Biología Molecular; 2014

Sociedad Argentina de Investigación en Bioquímica y Biología Molecular

The reversible phosphorylation of proteins on Ser/Thr-Pro motifs is a key signaling mechanism that controls various cellular processes, including cell division. The intervening peptide bond preceding Pro in Ser/Thr-Pro motifs may adopt two different conformations, cis and trans, whose conversion is specifically catalyzed by the prolyl isomerase Pin1 when Ser or Thr are phosphorylated, inducing conformational changes in target proteins that affect their catalytic activity, protein-protein interactions, subcellular location, and/or turnover. Pin1 is frequently overexpressed in human cancers and its overexpression correlates with poor prognosis. Thus, Pin1 has been proposed as a therapeutic target. In this work, we have analyzed the in vitro antitumor potential of the Pin1 inhibitor Juglone in combination with retinoic acid (RA), a drug used in clinical treatment of neuroblastoma and acute promyelocytic leukemia. Our results show that Juglone cooperates with RA to increase cytotoxicity in human adenocarcinoma cell line, MDA-MB-231. Furthermore, using neuroblastoma cell line Neuro-2a, the effects of Juglone in RA-neuronal differentiation as well as the effect of Pin1 overexpression have been analysed. Together, our results suggest that Pin1 has an inhibitory effect in RA-induced neuronal differentiation and suggest that its inhibition promotes the differentiation in the absence of RA.