Activation of three distinct RXR/RAR heterodimers induces growth arrest and differentiation of neuroblastoma cells.

Naturally occurring retinoids, like all-trans retinoic acid and 9-cis retinoic acid, are known to affect proliferation and differentiation of sensitive neuroblastoma cell lines. Cellular responsiveness to retinoic acid depends on its interaction with two distinct classes of receptors, the retinoic acid receptors (RARs) and the retinoic X receptors (RXRs). Both receptor classes have three different subtypes (RARalpha, RARbeta, and RARgamma and RXRalpha, RARbeta, and RARgamma) that act as ligand-dependent transcription factors. To examine the involvement of the different receptor classes and subtypes in the biological responses of neuroblastoma cells to retinoids, we analyzed the effects of a panel of receptor-selective retinoids on cell growth, differentiation, and gene expression on in vitro cultured KCNR cells. Any association of per se inactive RXR-selective with RAR-selective ligands efficiently regulates growth inhibition, differentiation (neurite extension), and expression of RARbeta, TrkB, and N-myc. SR11383 alone, a very potent retinoid, entirely reproduces the pattern of biological responses induced by naturally occurring retinoids. In contrast to other tumor cell lines, the growth of neuroblastoma cell lines is not altered using AP1-antagonistic retinoids. These studies raise the possibility that three distinct RXR/RAR heterodimers mediate the effects of retinoids on neuroblastoma cells through an AP-1 antagonism-independent mechanism.