Differential effects of retinol and retinoic acid on cell proliferation: a role for reactive species and redox-dependent mechanisms in retinol supplementation.
While some authors suggest that retinoids are potential anti-proliferative and antioxidant agents, evidence has suggested those present pro-oxidant properties, which might lead to malignant proliferation. These discordances stimulated one to investigate the proliferative/anti-proliferative properties of two major retinoids, retinol (ROH) and retinoic acid (RA). In Sertoli cells, ROH increased proliferation while RA was anti-proliferative. ROH increased DNA synthesis, decreased p21 levels and induced cell cycle progression. ROH increased reactive species (RS) production and stimulated p38, JNK1/2 and ERK1/2 MAPKs activation. Antioxidant treatment with Trolox blocked ROH-induced RS production, MAPKs activation and proliferation; MAPKs inhibition blocked proliferation. The potential sites of RS indicate that ROH-induced RS is promoted via mitochondria and xanthine oxidase. In contrast, RA induced neither RS production nor MAPKs activation. RA decreased DNA synthesis and increased p21 leading to cell arrest. Overall, data show that ROH, but not RA, is able to induce proliferation through non-classical and redox-dependent mechanisms.
Zanotto-Filho
Alfeu
A
Departamento de Bioquímica, Centro de Estudos em Estresse Oxidativo, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brasil.
Schröder
Rafael
R
Moreira
José Cláudio F
JC
D000818:Animals; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D020935:MAP Kinase Signaling System; D008297:Male; D008954:Models, Biological; D016877:Oxidants / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D017382:Reactive Oxygen Species; D012708:Sertoli Cells / Q000378:metabolism; D014801:Vitamin A / Q000378:metabolism*; D014969:Xanthine Oxidase / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D050759:Cyclin-Dependent Kinase Inhibitor p21; D016877:Oxidants; D017382:Reactive Oxygen Species; D014801:Vitamin A; D014969:Xanthine Oxidase; D048051:p38 Mitogen-Activated Protein Kinases