Retinoic acid induces neuroblastoma cell death by inhibiting proteasomal degradation of retinoic acid receptor alpha.
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 alpha (RAR-alpha) and underwent ATRA-induced cell death that was blocked by an RAR-alpha antagonist. By contrast, RAR-alpha 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-alpha expression during ATRA treatment. Our data suggest that SK-N-DZ cells have a defect in RAR-alpha down-regulation, resulting in sustained high expression of RAR-alpha 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-alpha 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-alpha degradation.
Nagai
Jun-ichi
J
Division of Laboratory Medicine, Clinical Research Institute, Kanagawa Children's Medical Center, Yokohama, Japan. j-nagai@cd5.so-net.ne.jp
Yazawa
Takuya
T
Okudela
Koji
K
Kigasawa
Hisato
H
Kitamura
Hitoshi
H
Osaka
Hitoshi
H
D001565:Benzoates / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002839:Chromans / Q000494:pharmacology; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D061988:Proteasome Inhibitors; D012333:RNA, Messenger / Q000032:analysis; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin / Q000494:pharmacology*; D025801:Ubiquitin / Q000378:metabolism
D001565:Benzoates; D002839:Chromans; D007976:Leupeptins; D061988:Proteasome Inhibitors; C000607071:RARA protein, human; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D025801:Ubiquitin; C084904:Ro 41-5253; D014212:Tretinoin; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde