Retinoid Inhibits Nrf2 Signaling Pathway through Retinoic Acid Receptor Alpha

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Retinoids, natural and synthetic signaling molecules that are structurally related to vitamin A. Compounds such as retinol, retinal, retinoic acid, retinyl esters and other derivatives are considered under the group of retinoids. Retinoids are significantly considered to be the most prominent regulators of several essential biological functions. For instance, active derivative of retinol (metabolite of Vitamin A) such as retinoic acid (RA) plays a major role in vision, cell differentiation, tissue homeostasis, apoptosis, organogenesis, regulation of immune system and embryonic pattern formation(1). In addition RA is also considered to be a potent chemopreventive and tumor suppressive agent because of its apoptotic and anti-oxidant activity. A wide variety of studies in animal models and clinical trials have shown the anticancer activity of RA against different types of cancers such as lymphoma, leukemia, melanoma, lung cancer, cervical cancer, kidney cancer, neuroblastoma, and glioblastoma (2). It has also been shown that RA promotes the generation of ROS including free radicals that drives the expression of antioxidant enzymes in rat sertoli cells and human retinal pigment epithelial cells (3) (4). Retinoids induce their physiological effects via interaction with two distinct classes of nuclear receptors including retinoic acid receptors (RAR) and retinoid X receptors (RXR). These two nuclear receptors belong to the members of steroid/thyroid hormone receptor superfamily (5) (6). All-trans-retenoic acid (ATRA) and 9-cis- retenoic acid (9CRA) are the two isomers of RA which acts as ligands and binds to the RAR and RXR nuclear receptors. Although, it’s well known that, 9CRA only binds with RXRs, where as both ATRA and 9CRA ligand... ... middle of paper ... ...tamin A-deficient (VAD) diet to know the specific antagonistic activity of RA on Nrf2. Interestingly, experimental data on western blotting of proteins in the small intestine of Nrf2 +/+ has shown an increase in the levels of Gstm5, GCLC, NQO1 and Gsta1/2 but not in the Nrf2 -/- mice. Moreover, the administration of ATRA to Nrf2 +/+ mice on the VAD diet has shown almost complete blockage in the increase in Gstm5, GCLC, NQO1, and Gsta1/2 proteins in the small intestine. This repression of ARE-driven gene expression strongly suggested the antagonistic role of ATRA on Nrf2. Altogether above findings suggested that, targeting the Nrf2 inhibition through RARα may become a novel therapeutic approach to encounter the drug resistance in tumor cells. However, further structural studies on Nrf2: RARα interactions are needed to know which domain of RARα could reacts with Nrf2.

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