Retinoic acid confers resistance to p53-dependent apoptosis in SH-SY5Y neuroblastoma cells by modulating nuclear import of p53

Many cell lines derived from neuroblastoma (NB) carry the wild-type p53 gen e with a p53-dependent apoptotic pathway that is responsive to DNA damaging agents. A recent study has demonstrated that retinoic acid (RA) pretreatme nt of NE cells promotes chemoresistance to apoptosis induced by chemotherap eutic agents. We examine here the possible contribution of the p53 pathway to the chemoresistance response associated with the RA treatment in NE cell s. Upon treatment with RA (1-10 mu M) for 4 days, the human NE cells, SH-SY 5Y, developed resistance selectively to p53-dependent apoptotic stimuli inc luding gamma-irradiation, etoposide, and 1-(5-isoquinolinyl sulfonyl)-2-met hylpiperazine (H-7). Interestingly, RA affected the ability of H-7 to induc e nuclear accumulation of the p53 protein without altering its effect on el evating the steady-state level of p53, suggesting that drug-induced up-regu lation and nuclear accumulation of the wild-type p53 protein are separable processes. The modulation of nuclear import of p53 protein by RA may thus r epresent a potential mechanism by which certain tumor cells with the wild-t ype p53 gene develop resistance to chemotherapeutic agents.