Molecular pathways: current role and future directions of the retinoic acid pathway in cancer prevention and treatment

Abstract

Retinoids and their naturally metabolized and synthetic products (e.g., all-trans retinoic acid, 13-cis retinoic acid, bexarotene) induce differentiation in various cell types. Retinoids exert their actions mainly through binding to the nuclear retinoic acid receptors (α, β, γ), which are transcriptional and homeostatic regulators with functions that are often compromised early in neoplastic transformation. The retinoids have been investigated extensively for their use in cancer prevention and treatment. Success has been achieved with their use in the treatment of subtypes of leukemia harboring chromosomal translocations. Promising results have been observed in the breast cancer prevention setting, where fenretinide prevention trials have provided a strong rationale for further investigation in young women at high risk for breast cancer. Ongoing phase III randomized trials investigating retinoids in combination with chemotherapy in non-small cell lung cancer aim to definitively characterize the role of retinoids in this tumor type. The limited treatment success observed to date in the prevention and treatment of solid tumors may relate to the frequent epigenetic silencing of RARβ. Robust evaluation of RARβ and downstream genes may permit optimized use of retinoids in the solid tumor arena.

Figure 1. The Retinoic Acid Receptors and their action

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.

Figure 2. Mechanism of activation of RARβ, an important downstream effector of the RA pathway, in cancer growth inhibition

Under conditions where RARα is functional and the RARβ promoter is not epigenetically silenced, physiological levels of RA can activate RARβ expression. A small number of solid tumors display this phenotype. Under less ideal conditions in which the RARβ promoter is hypoacetylated, pharmacological doses of RA are needed to activate RARβ. In the majority of solid tumor types, the RARβ promoter is methylated and/or the histones are significantly deacetylated. In this case, treatment with pharmacological doses of RA is not sufficient to overcome the repressive effect of epigenetic silencing. Epigenetic-modifying drugs such as DNA methytransferases or histone deacetylase (HDAC) inhibitors are needed to release the epigenetic stress and activate the RARβ gene. NCOR: nuclear receptor co-repressor 1; SMRT silencing mediator for retinoid and thyroid receptors