Retinol induces morphological alterations and proliferative focus formation through free radical-mediated activation of multiple signaling pathways

被引:8
作者
Gelain, Daniel Pens [1 ]
de Bittencourt Pasquali, Matheus Augusto [1 ]
Caregnato, Fernanda Freitas [1 ]
Alves Castro, Mauro Antonio [1 ]
Fonseca Moreira, Jose Claudio [1 ]
机构
[1] Univ Fed Rio Grande do Sul, Dept Biochem, Ctr Oxidat Stress Res, Porto Alegre, RS, Brazil
关键词
retinol; vitamin toxicity; Sertoli cell; oxidative stress; cell deformation; p38; JNK; Akt; ERK; PKC; PKA; VITAMIN-A SUPPLEMENTATION; GLYCATION ENDPRODUCTS RAGE; CULTURED SERTOLI-CELLS; OXIDATIVE STRESS; BETA-CAROTENE; LUNG-CANCER; DNA-DAMAGE; ACID; PHOSPHORYLATION; CARCINOMA;
D O I
10.1038/aps.2011.202
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Aim: Toxicity of retinol (vitamin A) has been previously associated with apoptosis and/or cell malignant transformation. Thus, we investigated the pathways involved in the induction of proliferation, deformation and proliferative focus formation by retinol in cultured Sertoli cells of rats. Methods: Sertoli cells were isolated from immature rats and cultured. The cells were subjected to a 24-h treatment with different concentrations of retinol. Parameters of oxidative stress and cytotoxicity were analyzed. The effects of the p38 inhibitor SB203580 (10 pmol/L), the JNK inhibitor SP600125 (10 pmol/L), the Akt inhibitor LY294002 (10 pmol/L), the ERK inhibitor U0126 (10 pmol/L) the pan-PKC inhibitor GO6983 (10 pmol/L) and the PKA inhibitor H89 (1 pmol/L) on morphological and proliferative/transformationassociated modifications were studied. Results: Retinol (7 and 14 pmol/L) significantly increases the reactive species production in Sertoli cells. Inhibition of p38, JNK, ERK1/2, Akt, and PKA suppressed retinol-induced [31d]cIT incorporation into the cells, while PKC inhibition had no effect. ERK1/2 and p38 inhibition also blocked retinol-induced proliferative focus formation in the cells, while Akt and JNK inhibition partially decreased focus formation. ERK1/2 and p38 inhibition hindered transformation-associated deformation in retinol-treated cells, while other treatments had no effect. Conclusion: Our results suggest that activation of multiple kinases is responsible for morphological and proliferative changes associated to malignancy development in Sertoli cells' by retinol at the concentrations higher than physiological level.
引用
收藏
页码:558 / 567
页数:10
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