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Increased retinoic acid receptor beta (RARbeta(2)) gene expression is a hallmark of cancer cell responsiveness to retinoid anticancer effects. Moreover, low basal or induced RARbeta(2) expression is a common feature of many human cancers, suggesting that RARbeta(2) may act as a tumour suppressor gene in the absence of supplemented retinoid. We have previously shown that low RARbeta(2) expression is a feature of advanced neuroblastoma. Here, we demonstrate that the ABC domain of the RARbeta(2) protein alone was sufficient for the growth inhibitory effects of RARbeta(2) on neuroblastoma cells. ATP7A, the copper efflux pump, is a retinoid-responsive gene, was upregulated by ectopic overexpression of RARbeta(2). The ectopic overexpression of the RARbeta(2) ABC domain was sufficient to induce ATP7A expression, whereas, RARbeta(2) siRNA blocked the induction of ATP7A expression in retinoid-treated neuroblastoma cells. Forced downregulation of ATP7A reduced copper efflux and increased viability of retinoid-treated neuroblastoma cells. Copper supplementation enhanced cell growth and reduced retinoid-responsiveness, whereas copper chelation reduced the viability and proliferative capacity. Taken together, our data demonstrates ATP7A expression is regulated by retinoic acid receptor beta and it has effects on intracellular copper levels, revealing a link between the anticancer action of retinoids and copper metabolism.

ATP7A is a novel target of retinoic acid receptor β2 in neuroblastoma cells