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

A. Bohlken, B. B. Cheung, D. R. Richardson, G. M. Marshall, J. L. Bell, J. Koach, S. Smith, E. Sekyere, W. Thomas, M. Norris, M. Haber, D. B. Lovejoy

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)96-105
Number of pages10
JournalBritish Journal of Cancer
Volume100
Issue number1
DOIs
Publication statusPublished - 2009
Externally publishedYes

Keywords

  • ATP7A
  • Copper and neuroblastoma
  • Retinoic acid receptor ?2
  • Retinoids

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