Increased retinoic acid receptor β (RARβ₂) gene expression is a hallmark of cancer cell responsiveness to retinoid anticancer effects. Moreover, low basal or induced RARβ2 expression is a common feature of many human cancers, suggesting that RARβ₂ may act as a tumour suppressor gene in the absence of supplemented retinoid. We have previously shown that low RARβ₂ expression is a feature of advanced neuroblastoma. Here, we demonstrate that the ABC domain of the RARβ₂ protein alone was sufficient for the growth inhibitory effects of RARβ₂ on neuroblastoma cells. ATP7A, the copper efflux pump, is a retinoid-responsive gene, was upregulated by ectopic overexpression of RARβ₂. The ectopic overexpression of the RARβ₂ ABC domain was sufficient to induce ATP7A expression, whereas, RARβ₂ 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 β and it has effects on intracellular copper levels, revealing a link between the anticancer action of retinoids and copper metabolism.
- Copper and neuroblastoma
- Retinoic acid receptor ?2