Abstract
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.
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Abbreviations
- RA:
-
retinoic acid
- RAR:
-
RA receptor
- RARE:
-
RA response element
- p53RE:
-
p53 response element
- Cdk:
-
cyclin dependent kinase
- CdkI:
-
Cdk inhibitor
- CIT:
-
CD437-induced transcript
- Luc:
-
Luciferase
- 4NQ:
-
4-nitroquinoline N-oxide
- DMSO:
-
dimethyl sulfoxide
- PI:
-
propidium iodide
- PARP:
-
poly (ADP ribose) polymerase
- SDS–PAGE:
-
sodium dodecylsulfate-polyacrylamide gel electrophoresis
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Acknowledgements
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).
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Zhao, X., Demary, K., Wong, L. et al. Retinoic acid receptor-independent mechanism of apoptosis of melanoma cells by the retinoid CD437 (AHPN). Cell Death Differ 8, 878–886 (2001). https://doi.org/10.1038/sj.cdd.4400894
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DOI: https://doi.org/10.1038/sj.cdd.4400894
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