Retinoic Acid Increases the Expression of p53 and Proapoptotic Caspases and Sensitizes Keratinocytes to Apoptosis

Autor:	Michael Rendl, Erwin Tschachler, Claudia Ballaun, Florian Gruber, Barbara Lengauer, Leopold Eckhart, Paul Mrass, Michael Mildner
Rok vydání:	2004
Předmět:	Cancer Research Programmed cell death integumentary system biology Tumor suppressor gene medicine.drug_class Retinoic acid chemistry.chemical_compound medicine.anatomical_structure Oncology chemistry Apoptosis medicine biology.protein Cancer research DNA fragmentation Retinoid Keratinocyte Caspase
Zdroj:	Cancer Research. 64:6542-6548
ISSN:	1538-7445 0008-5472
DOI:	10.1158/0008-5472.can-04-1129
Popis:	Retinoids influence growth and differentiation of keratinocytes (KCs) and are widely used for the management of skin diseases and for prevention of nonmelanoma skin cancer (NMSC) in predisposed patients. Here we investigated the effect of all-trans-retinoic acid (ATRA) on KC apoptosis. When KCs were cultured in confluent monolayers for several days, they acquired resistance against UVB-induced apoptosis. In contrast, when the cells were treated with 1 μmol/L ATRA for 6 days and subsequently irradiated with different doses of UVB, they underwent massive apoptosis as assessed by morphology, expression of activated caspase-3, and DNA fragmentation. The same effect was observed when doxorubicin was used instead of UVB. Analysis by real-time PCR and Western blot revealed that ATRA treatment strongly increased the mRNA and protein expression of p53 and caspase-3, -6, -7, and -9, which are key regulators of apoptosis. UVB irradiation of ATRA-treated cells but not of control cells led to the accumulation of p53 protein and of its target gene Noxa. Inhibition of p53 and caspases with α-pifithrin and z-Val-Ala-Asp-fluoromethyl ketone, respectively, blocked UVB- and doxorubicin-induced apoptosis in ATRA-treated KCs. Analogous to the observed ATRA effects in monolayer cultures, in vitro-generated organotypic skin cultures reacted with up-regulation of p53 and proapoptotic caspases and displayed increased sensitivity to UVB-induced apoptosis. The ability of retinoic acid to regulate the expression of proapoptotic genes and to sensitize KCs to apoptosis may play a role in their prevention of NMSC in transplant patients and patients with DNA-repair deficiencies.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_________::52b574cec0e86f28092ee8b9e43cb2ee https://doi.org/10.1158/0008-5472.can-04-1129 Zobrazit plný text záznamu