Retinoic acid receptor-independent mechanism of apoptosis of melanoma cells by the retinoid CD437 (AHPN).
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.
Zhao
X
X
Department of Otolaryngology, Cancer Research Center, Boston University School of Medicine, 75 Albany Street R903, Boston, MA 02118, USA.
Demary
K
K
Wong
L
L
Vaziri
C
C
McKenzie
A B
AB
Eberlein
T J
TJ
Spanjaard
R A
RA
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
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