Proliferation-dependent induction of apoptosis by the retinoid CD437 in p53-mutated keratinocytes.
J Mol Med (Berl)
; 80(1): 61-7, 2002 Jan.
Article
in En
| MEDLINE
| ID: mdl-11862326
ABSTRACT
6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-Naphthalene carboxylic acid (CD437) is a synthetic retinoid with strong apoptogenic properties in various neoplastic cell lines. CD437 was shown to induce apoptosis in malignant human keratinocytes but not in normal keratinocytes. We demonstrate that CD437 is also capable of inducing apoptosis in the non-tumorigenic keratinocyte cell line HaCaT that carries UV-type mutations on both alleles of the p53 gene. The concentration-dependent induction of apoptosis was restricted to proliferative HaCaT cells, whereas no effect was seen in differentiating post-mitotic cells. The apoptotic elimination of the proliferative cells was accompanied by rapid upregulation of c- jun, downregulation of c- fos, and activation of the AP-1 complex, which normally only occur during the differentiation process of post-mitotic keratinocytes. Pharmacological impairment of this precocious AP-1 activation reduced the rate of apoptosis induced by CD437. The potent, selective, and p53-independent apoptosis-inducing efficacy of CD437 is of utmost importance for the prophylaxis and treatment of skin cancer caused by mutational inactivation of the p53 gene.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Retinoids
/
Keratinocytes
/
Tumor Suppressor Protein p53
/
Apoptosis
Limits:
Humans
Language:
En
Journal:
J Mol Med (Berl)
Journal subject:
BIOLOGIA MOLECULAR
/
GENETICA MEDICA
Year:
2002
Document type:
Article
Affiliation country:
Alemania