In a series of enzymatic steps, Vitamin A (retinol) is metabolized through the oxidizing action of retinaldehyde (RDH) to retinal, and by retinaldehyde dehydrogenase (RALDH) to retinoic acid (RA). RA has three different isomers including all-trans, 9-cis, and 13-cis-retinoic acids. Retinoic acid is transported to the nucleus by the protein Cellular Retinoic Acid Binding Protein (CRABP) and delivered to the retinoic acid receptor α (RARα). RARα heterodimerizes with, and binds to RA responsive elements (RARE) present most often in gene promoters. In the classical pathway of RA action, RA binds to dimers of RARα and rexinoid receptors (RXR α, β, or γ) to induce expression of its downstream target genes, including RARβ. Upon activation, RARβ can regulate its own expression and that of its downstream genes, which function are mainly to inhibit cell growth. Alternatively, RA can be bound and transported to the nucleus by other factors such as FABP5. This delivers RA to other non-classical receptors such as PPARβ/δ and ERα which activate non-genomic pathways such as PDK-1/Akt or the ERα pathway. Contrary to the differentiation functions attributed to the classical pathway, the non-genomic pathways exert strong anti-apoptotic and proliferative effects on cancer cells. It is believed that the classical and non-genomic pathways are controlled by the relative abundance of their own ligands. RA has a stronger affinity for RARs compared to the other receptors and the classical pathway plays a dominant role over the non-genomic pathways. Thus, if RA is present with other ligands such as estrogen, signaling through the classical pathway is preferred to result in cell differentiation and growth inhibition.
