title: Retinoic acid receptor-independent mechanism of apoptosis of melanoma cells by the retinoid CD437 (AHPN).
abstract: Retinoic acid (RA) induces differentiation of S91 melanoma cells through activation of RA receptor (RAR)gamma without affecting cell viability. The novel RARgamma-agonist CD437 (AHPN), however, also induces concomitant apoptosis through an unknown mechanism which was investigated here. By utilizing DNA microarray analysis, five apoptosis-associated, CD437-induced transcripts (CITs) were identified. Interestingly, all CITs are also regulated by p53 in a DNA damage response, and consistent with this interpretation, CD437 was found to cause DNA adduct-formation. However, p53 is not required for CD437-dependent regulation of CITs. Among this set of genes, induction of p21(WAF1/CIP1) is likely to be responsible for early S-phase growth-arrest of CD437-treated cells, whereas ei24 is a critical mediator of CD437-induced apoptosis in S91 cells. These data suggest an RAR-independent mechanism in which CD437 causes DNA adduct-formation, resulting in induction of a p53-independent DNA damage response, and subsequent growth-arrest and apoptosis. CD437-mediated DNA adduct-formation may also explain its apoptotic effects in other cell types.
authors.affiliation: Department of Otolaryngology, Cancer Research Center, Boston University School of Medicine, 75 Albany Street R903, Boston, MA 02118, USA.
authors.forename: X
authors.initials: X
authors.lastname: Zhao
authors.forename: K
authors.initials: K
authors.lastname: Demary
authors.forename: L
authors.initials: L
authors.lastname: Wong
authors.forename: C
authors.initials: C
authors.lastname: Vaziri
authors.forename: A B
authors.initials: AB
authors.lastname: McKenzie
authors.forename: T J
authors.initials: TJ
authors.lastname: Eberlein
authors.forename: R A
authors.initials: RA
authors.lastname: Spanjaard
mesh_terms: D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D002455:Cell Division / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D018736:DNA Adducts / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D008546:Melanoma, Experimental / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D016376:Oligonucleotides, Antisense / Q000235:genetics; D009928:Organ Specificity; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D012176:Retinoids / Q000494:pharmacology*; D016196:S Phase / Q000187:drug effects; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
chemical_list: D051017:Apoptosis Regulatory Proteins; C099555:CD 437; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D018736:DNA Adducts; C402592:EI24 protein, human; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense; D010750:Phosphoproteins; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D016159:Tumor Suppressor Protein p53