Transcriptional Upregulation of Retinoic Acid Receptor β (RARβ) Expression by Phenylacetate in Human Neuroblastoma Cells (original) (raw)

1998, Experimental Cell Research

NaPA) 2 both stimulates the differentiation of neuro-Sodium phenylacetate (NaPA) has been shown to blastoma cells by itself and acts synergistically with synergize with retinoic acid (RA) in inducing the dif-retinoic acid (RA). Thus, combination treatment with ferentiation of human neuroblastoma cells. Our stud-NaPA and RA at concentrations that were saturating ies indicated that NaPA can impact on the RA differin terms of a biological response with each agent alone entiation program by upregulating nuclear retinoic caused further marked enhancement of all parameters acid receptor-b (RARb) expression. We have found measured. In our experience, the combined effects of that NaPA does not alter the half-life of RARb mRNA; NaPA and RA have shown the strongest differentiation thus, increased stability of mRNA levels does not coninduction we have yet observed by neuroblastoma cells, tribute to NaPA induction. In contrast, NaPA was able in terms of both number of cells responding and matuto specifically activate a reporter gene construct ration level achieved. (DSVbRE-CAT) which contains a retinoic acid re-We have also demonstrated that NaPA can ''prime'' sponse element (RARE b) that is located in the RARb cells for subsequent induction by RA [3]. These experipromoter. Activation of DSVbRE-CAT by NaPA also ments have suggested that differentiation in the presoccurred in neuroblastoma cells cotransfected with a ence of both agents includes NaPA-induced effects that nuclear retinoic acid receptor expression vector, directly impact on the RA differentiation pathway and demonstrating the independence of this activation on require only relatively short priming periods, as well cellular RAR levels. Taken together, our findings sugas RA-independent effects of NaPA which require the gest that induction of RARb by NaPA is regulated at continued presence of this compound. One example of the level of transcription and mediated through the this former activity is illustrated by the finding that retinoic acid response element, RARE b. This effect NaPA can activate nuclear retinoic acid receptor-b may account, at least in part, for the strong synergy (RARb) expression, which occurs after only 1 day of between NaPA and RA in promoting neuroblastoma NaPA treatment [3]. This effect appeared to be distinct differentiation. ᭧ 1998 Academic Press from the ability of NaPA to alter tumor cell lipid metabolism via inhibition of protein isoprenylation. Interaction of NaPA with RA via upregulation of RARb expres-1 To whom correspondence and reprint requests should be ad-2 Abbreviations used: NaPA, sodium phenylacetate; RA, all-trans-dressed at Department of Gynecology and Obstetrics, Woodruff Memorial Research Building, 1639 Pierce Drive, Emory University retinoic acid; RARb, nuclear retinoic acid receptor-b; RARE b , retinoic acid response element-b; CAT, chloramphenicol acetyltransferase.