Effect of retinoic acid isomers on the neuronal differentiation of human neuroblastoma cells

Abstract

Retinoic acid (RA), a derivative of vitamin A, is essential for maintaining normal growth and development. RA inhibits cellular proliferation and induces differentiation or apoptosis of many cancer cells. Clinically, RA is an effective therapeutic agent for the acute promyelocytic leukemia. Hence, understanding the mode of action of RA has important biologic implications. In this study, we examined the effectiveness of 3 RA isomers, all-trans (t-), 9-cis (9c-), and 13-cis (13c-) RA, on the proliferation and differentiation of neuroblastoma cells (IMR-32). Continuous treatment of IMR-32 cells with the RA isomers at concentration of 1 μM for 10 days resulted in similar inhibition of cell proliferation and differentiation into neuron-like cells. However, 13c-RA induced higher expression of neurofilament, suggesting that 13c-RA was more potent in mediating neuronal differentiation. To identify the possible mechanism underlying the differential efficacy of RA isomers, we examined the effect of RA treatment on the expression of RA receptors (RARs) and retinoid X receptors (RXRs) in IMR-32 cells. It was demonstrated that 13c-RA induced higher expression of RARβ, and RXRβ1. Expression of other RARs and RXRs was regulated similarly by 13c-, 9c- and t-RA. Thus, the differential efficacy of RA isomers could not be completely explained by the differential expression of their cognate receptors. Our data suggested that other signaling molecules, such as MAP kinases, might have responded differently to the RA isomers. Thus, the RA isomers may recruit different signaling intermediates in mediating their specific biological actions. Supported by The Kadoorie Charitable Foundation