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

Abstract

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 μmol/L), the JNK inhibitor SP600125 (10 μmol/L), the Akt inhibitor LY294002 (10 μmol/L), the ERK inhibitor U0126 (10 μmol/L) the pan-PKC inhibitor GÖ6983 (10 μmol/L) and the PKA inhibitor H89 (1 μmol/L) on morphological and proliferative/transformationassociated modifications were studied. Results: Retinol (7 and 14 μmol/L) significantly increases the reactive species production in Sertoli cells. Inhibition of p38, JNK, ERK1/2, Akt, and PKA suppressed retinol-induced [ 3 H]dT 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.

Causal associations between dietary antioxidant vitamin intake and lung cancer: A Mendelian randomization study

“…Previous studies suggest that retinol may enhance free radical production, leading to phosphorylation of Src-tyrosine kinase, MAPK/ERK kinases 1/2 (MEK1/2), cAMP-responsive element binding protein (CREB), and extracellular signal-regulated kinases 1 and 2 (ERK1/2). The activation of this pathway appears to be involved in the onset of some of the deleterious effects, such as malignant transformation and cell proliferation (69,70).…”

Chronic retinyl palmitate supplementation to middle‐aged Wistar rats disrupts the brain redox homeostasis and induces changes in emotional behavior

“…It is also known that nongenomic actions can influence brain functioning, affecting synaptic transmission, catecholamine production in the brain, cell‐cycle regulation mediated by mitogen‐activated protein kinase (MAPK), protein kinase B (PKB), and protein kinase C activation . However, it was recently demonstrated that retinol‐induced ROS production in Sertoli cells is able to activate different pathways of protein kinases, including MAPKs, extracellular‐signal‐regulated kinases (ERK1/2), c‐Jun N‐terminal kinases, and PKB . Thus, the oxidative stress observed in the brain of middle‐aged Wistar rats after the chronic supplementation of moderate amounts of vitamin A may also have a deleterious effect upon important cell signaling pathways.…”

Mychonastes sp. 247 Induces Apoptosis of A549 Human Lung Cancer Cells by Promoting STRA6-Mediated Reactive Oxygen Species Production

“…Additionally, the effect of retinol on oxidative stress remains controversial. [35][36][37] However, STRA6, the receptor for retinoic acid uptake, induces mitochondrial depolarization and intracellular ROS. 19,38 In the present study, treatment with ME increased the mRNA and protein levels of STRA6 and increased intracellular ROS levels via mitochondrial dysfunction.…”