ABSTRACT
Retinoic acid (RA) has been approved for the differentiation therapy of neuroblastoma (NB). Previous work revealed a correlation between glucose-regulated protein 75 (GRP75) and the RA-elicited neuronal differentiation of NB cells. The present study further demonstrated that GRP75 translocates into the nucleus and physically interacts with retinoid receptors (RARα and RXRα) to augment RA-elicited neuronal differentiation. GRP75 was required for RARα/RXRα-mediated transcriptional regulation and was shown to reduce the proteasome-mediated degradation of RARα/RXRαin a RA-dependent manner. More intriguingly, the level of GRP75/RARα/RXRα tripartite complexes was tightly associated with the RA-induced suppression of tumor growth in animals and the histological grade of differentiation in human NB tumors. The formation of GRP75/RARα/RXRα complexes was intimately correlated with a normal MYCN copy number of NB tumors, possibly implicating a favorable prognosis of NB tumors. The present findings reveal a novel function of nucleus-localized GRP75 in actively promoting neuronal differentiation, delineating the mode of action for the differentiation therapy of NB by RA.
Nuclear GRP75 binds retinoic acid receptors to promote neuronal differentiation of neuroblastoma
Riferimento:
PLoS One. 2011;6(10):e26236.
Autori:
Shih YY, Lee H, Nakagawara A, Juan HF, Jeng YM, Tsay YG, Lin DT, Hsieh FJ, Pan CY, Hsu WM, Liao YF.
Fonte:
PLoS One. 2011;6(10):e26236.
Anno:
2011
Azione:
L'acido retinoico (RA) è stato approvato per la terapia di differenziazione del neuroblastoma (NB).
Target:
RA/neuroblastoma.
Sostanze: