Vitamin A (retinol) downregulates the receptor for advanced glycation endproducts (RAGE) by oxidant-dependent activation of p38 MAPK and NF-kB in human lung cancer A549 cells
Vitamin A (retinol) downregulates the receptor for advanced glycation endproducts (RAGE) by oxidant-dependent activation of p38 MAPK and NF-kB in human lung cancer A549 cells
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DOI：
10.1016/j.cellsig.2013.01.013
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发表时间：
2013-04-01
影响因子：
4.8
通讯作者：
Fonseca Moreira, Jose Claudio
中科院分区：
文献类型：
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作者：
de Bittencourt Pasquali, Matheus Augusto;Gelain, Daniel Pens;Fonseca Moreira, Jose Claudio
作为饮食的重要组成部分，视黄醇补充剂通常被认为是无害的，其应用控制不良。然而，最近的工作表明，视黄醇可能会引起广泛的有害影响，特别是当使用的剂量增加时。对照临床试验表明，补充视黄醇会增加吸烟者肺癌的发病率和死亡率。在细胞培养和动物模型中的实验工作表明，视黄醇可诱导自由基的产生，氧化应激和广泛的生物分子损伤。在这里，我们评估了视黄醇对人肺癌细胞系A549中晚期糖基化终末产物（AGEs）受体的调节作用。在肺中组成型表达，并观察到在肺癌患者中下调。A549细胞用报道为生理剂量（2 μ M）或治疗剂量（5、10或20 μ M）的视黄醇处理。视黄醇在10和20 μ M增加自由基的产生，氧化损伤和抗氧化酶的活性在A549细胞。这些剂量也下调了α表达。与Trolox（R）（α-生育酚的亲水性类似物）一起进行抗氧化剂共处理，逆转了视黄醇对氧化参数和β-生育酚下调的影响。视黄醇对p38 MAPK活化的作用是通过p38 MAPK活化介导的，因为用P13169316（10 μ M）、SB 203580（10 μ M）或针对p38 a（MAPK 14）或p3813（MAPK 11）的siRNA阻断p38可逆转视黄醇对p38 MAPK活化的作用。Trolox还抑制p38磷酸化，表明视黄醇诱导了这种MAPK的氧化还原依赖性激活。此外，我们观察到NF-κ B作为p38的下游效应物在视黄醇下调p53中起作用，因为SN 50（100 μ g/mL）和针对p65的siRNA抑制NF-κ B阻断了视黄醇对p53的作用，而p38抑制剂逆转了NF-κ B的活化。综上所述，我们的研究结果表明，视黄醇对A549细胞的促氧化作用，并表明，视黄醇的p38/NF-κ B信号通路的氧化还原依赖性激活介导的p38/NF-κ B表达的调制。(C)2013 Elsevier Inc. All rights reserved.
As an essential component of the diet, retinol supplementation is often considered harmless and its application is poorly controlled. However, recent works demonstrated that retinol may induce a wide array of deleterious effects, especially when doses used are elevated. Controlled clinical trials have demonstrated that retinol supplementation increased the incidence of lung cancer and mortality in smokers. Experimental works in cell cultures and animal models showed that retinol may induce free radical production, oxidative stress and extensive biomolecular damage. Here, we evaluated the effect of retinol on the regulation of the receptor for advanced glycation end-products (RAGE) in the human lung cancer cell line A549. RAGE is constitutively expressed in lungs and was observed to be down-regulated in lung cancer patients. A549 cells were treated with retinol doses reported as physiologic (2 mu M) or therapeutic (5, 10 or 20 mu M). Retinol at 10 and 20 mu M increased free radical production, oxidative damage and antioxidant enzyme activity in A549 cells. These doses also downregulated RAGE expression. Antioxidant co-treatment with Trolox (R), a hydrophilic analog of alpha-tocopherol, reversed the effects of retinol on oxidative parameters and RAGE downregulation. The effect of retinol on RAGE was mediated by p38 MAPK activation, as blockade of p38 with P13169316(10 mu M), SB203580 (10 mu M) or siRNA to either p38a (MAPK14) or p3813 (MAPK11) reversed the effect of retinol on RAGE. Trolox also inhibited p38 phosphorylation, indicating that retinol induced a redox-dependent activation of this MAPK. Besides, we observed that NF-kB acted as a downstream effector of p38 in RAGE downregulation by retinol, as NF-kB inhibition by SN50 (100 mu g/mL) and siRNA to p65 blocked the effect of retinol on RAGE, and p38 inhibitors reversed NF-kB activation. Taken together, our results indicate a pro-oxidant effect of retinol on A549 cells, and suggest that modulation of RAGE expression by retinol is mediated by the redox-dependent activation of p38/NF-kB signaling pathway. (C) 2013 Elsevier Inc. All rights reserved.