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Retinoic Acid Induces Neuroblastoma Cell Death by Inhibiting Proteasomal Degradation of Retinoic Acid Receptor

Divisions of ¹ Laboratory Medicine and ² Neurology, Clinical Research Institute, Kanagawa Children’s Medical Center, Yokohama, Japan; ³ Division of Cellular Pathobiology, Department of Pathology, Yokohama City University Graduate School of Medicine, Yokohama, Japan; ⁴ Biology Division, National Cancer Center Research Institute, Tokyo, Japan; and ⁵ Information and Cellular Function, PRESTO, Japan Science and Technology Agency (JST), Kawaguchi, Japan

To seek a novel therapeutic approach to neuroblastoma (NBL), we used three NBL cell lines (SK-N-DZ, NH12, and SK-N-SH) to examine the underlining molecular mechanisms of cellular reactions and sensitivity to all-trans-retinoic acid (ATRA). SK-N-DZ cells expressed relatively high levels of retinoic acid receptor (RAR-) and underwent ATRA-induced cell death that was blocked by an RAR- antagonist. By contrast, RAR- expression gradually decreased in NH12 and SK-N-SH cells, which did not experience increased cell death in response to ATRA. We report here the ubiquitin-dependent down-regulation of RAR- expression during ATRA treatment. Our data suggest that SK-N-DZ cells have a defect in RAR- down-regulation, resulting in sustained high expression of RAR- that confers high sensitivity to ATRA. Accordingly, treatment with a proteasome inhibitor dramatically increased ATRA-induced cell death in NH12 and SK-N-SH cell lines. Our results reveal the crucial involvement of the RAR- signaling pathway in NBL cell death and show that three NBL cell lines are differentially sensitive to ATRA. These data suggest a potential novel therapy for NBL involving retinoic acid treatment combined with the inhibition of RAR- degradation.

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