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 whose functions are often compromised early in neoplastic transformation. The retinoids have been investigated extensively for their utility 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 3 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.

E2F1 impairs all-trans retinoic acid-induced osteogenic differentiation of osteosarcoma via promoting ubiquitination-mediated degradation of RARα

“…[31][32][33] For example, Kaposi sarcoma and headand-neck cancer have already been treated with ATRA-based therapies. 34,35 Retinoids are clearly a promising class of compounds that will greatly enlarge our arsenal in the fight against cancer.…”

Histone Deacetylases as New Therapeutic Targets in Triple-negative Breast Cancer: Progress and Promises

“…Previous studies have reported that retinoic acid and its products, such as all-trans retinoic acid (ATRA), urge the differentiation of multiple types of stem cells, including the stem cells that exist in BC (130,131). On the other hand, ATRA has been used in a clinical trial and its efficacy was limited (132), possibly because of the epigenetic knock-out of the retinoic acid receptor (RAR)-β (133). Recent studies have shown that HDAC inhibitors have the ability to re-express RAR-β, so they restore the sensitivity of the cells to treatment (134)(135)(136).…”

Inhibitory effects of Actinidia Chinensis planch root extracts (acRoots) on human lung cancer cells through retinoic acid receptor beta

“…RARB is one of critical ligand-regulated transcription factors to centralize the cancer cell growth and metastasis through the RA and retinoid signaling pathways [11]. RARB was suggested as a potential therapeutic target to protect from solid tumors by the frequent epigenetic silencing of RARB [12]. Comprehensive expression of retinoic acid receptors in non-small cell lung cancer tissue was about up to 60% lower than in the normal [13], while extensive retinoidbased therapies, e.g.…”