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

• Published in: Cellular signalling 2013-04, Vol.25 (4), p.939-954
• Main Authors: de Bittencourt Pasquali, Matheus Augusto, Gelain, Daniel Pens, Zeidán-Chuliá, Fares, Pires, André Simões, Gasparotto, Juciano, Terra, Silvia Resende, Moreira, José Cláudio Fonseca
• Format: Article
• Language: English
• Subjects: Activation; alpha-Tocopherol - pharmacology; Antioxidants; Antioxidants - pharmacology; Cancer; Cell Line, Tumor; Damage; Down-Regulation - drug effects; Free radicals; Humans; Imidazoles - pharmacology; Inhibitors; Lung; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Lungs; Mitogen-Activated Protein Kinase 11 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 11 - genetics; Mitogen-Activated Protein Kinase 11 - metabolism; Mitogen-Activated Protein Kinase 14 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 14 - genetics; Mitogen-Activated Protein Kinase 14 - metabolism; NF-kappa B - antagonists & inhibitors; NF-kappa B - metabolism; Oxidation-Reduction; Oxidative stress; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - genetics; p38 Mitogen-Activated Protein Kinases - metabolism; p38/MAPK, NF-kB; Peptides - pharmacology; Phosphorylation - drug effects; Pyridines - pharmacology; RAGE; Receptor for Advanced Glycation End Products; Receptors; Receptors, Immunologic - metabolism; Retinol; RNA Interference; RNA, Small Interfering - metabolism; Signal Transduction - drug effects; Transcription Factor RelA - metabolism; Vitamin A - pharmacology
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2013.01.013

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 (2μM) or therapeutic (5, 10 or 20μM). Retinol at 10 and 20μM increased free radical production, oxidative damage and antioxidant enzyme activity in A549 cells. These doses also downregulated RAGE expression. Antioxidant co-treatment with Trolox®, a hydrophilic analog of α-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 PD169316 (10μM), SB203580 (10μM) or siRNA to either p38α (MAPK14) or p38β (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 (100μg/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. ► RAGE and retinol are involved in lung cancer. ► Retinol activated ROS production, p38, NF-kB and downregulated RAGE ► RAGE is inhibited by redox-dependent p38 and NF-kB activation in lung cancer cells. ► Evidences a redox mechanism of RAGE regulation in lung cancer cells by vitamin A