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

Increased retinoic acid receptor β (RAR β 2 ) gene expression is a hallmark of cancer cell responsiveness to retinoid anticancer effects. Moreover, low basal or induced RAR β 2 expression is a common feature of many human cancers, suggesting that RAR β 2 may act as a tumour suppressor gene in the ab...

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Bibliographic Details
Published in:British journal of cancer 2009-01, Vol.100 (1), p.96-105
Main Authors: Bohlken, A, Cheung, B B, Bell, J L, Koach, J, Smith, S, Sekyere, E, Thomas, W, Norris, M, Haber, M, Lovejoy, D B, Richardson, D R, Marshall, G M
Format: Article
Language:English
Subjects:
Biological and medical sciences
Biomedical and Life Sciences
Biomedicine
Cancer Research
Drug Resistance
Epidemiology
Medical sciences
Molecular Medicine
Neurology
Oncology
Translational Therapeutics
Tumors
Tumors of the nervous system. Phacomatoses
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Summary:Increased retinoic acid receptor β (RAR β 2 ) gene expression is a hallmark of cancer cell responsiveness to retinoid anticancer effects. Moreover, low basal or induced RAR β 2 expression is a common feature of many human cancers, suggesting that RAR β 2 may act as a tumour suppressor gene in the absence of supplemented retinoid. We have previously shown that low RAR β 2 expression is a feature of advanced neuroblastoma. Here, we demonstrate that the ABC domain of the RAR β 2 protein alone was sufficient for the growth inhibitory effects of RAR β 2 on neuroblastoma cells. ATP7A, the copper efflux pump, is a retinoid-responsive gene, was upregulated by ectopic overexpression of RAR β 2 . The ectopic overexpression of the RAR β 2 ABC domain was sufficient to induce ATP7A expression, whereas, RAR β 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 β and it has effects on intracellular copper levels, revealing a link between the anticancer action of retinoids and copper metabolism.
ISSN:0007-0920
1532-1827
DOI:10.1038/sj.bjc.6604833