TY - JOUR
T1 - Retinoic acid receptor-independent mechanism of apoptosis of melanoma cells by the retinoid CD437 (AHPN)
AU - Zhao, X.
AU - Demary, K.
AU - Wong, L.
AU - Vaziri, C.
AU - McKenzie, A. B.
AU - Eberlein, T. J.
AU - Spanjaard, R. A.
N1 - Funding Information:
We thank Douglas Faller for insightful comments, and Andrew Hsing and James Liu for technical assistance. This work was supported by a research grant from the National Institutes of Health CA76406 (to RA Spanjaard).
PY - 2001
Y1 - 2001
N2 - Retinoic acid (RA) induces differentiation of S91 melanoma cells through activation of RA receptor (RAR)γ without affecting cell viability. The novel RARγ-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 p21WAF1/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.
AB - Retinoic acid (RA) induces differentiation of S91 melanoma cells through activation of RA receptor (RAR)γ without affecting cell viability. The novel RARγ-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 p21WAF1/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.
KW - Apoptosis
KW - CD437
KW - Differentiation
KW - Melanoma
KW - Retinoic acid receptor
UR - http://www.scopus.com/inward/record.url?scp=0034874421&partnerID=8YFLogxK
U2 - 10.1038/sj.cdd.4400894
DO - 10.1038/sj.cdd.4400894
M3 - Article
C2 - 11526443
AN - SCOPUS:0034874421
VL - 8
SP - 878
EP - 886
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
SN - 1350-9047
IS - 9
ER -