Retinoids and retinoic acid receptor in cancer
Abstract
Retinoids are vitamin A derivatives that exert major effects on growth control, epithelial differentiation and embryonic development and, accordingly, are highly teratogenic.
In HL60 myelo-monocytic or F9 embryonal carcinoma cell lines, retinoic acid (RA) turns a transformed cell line into terminally differentiated non-proliferating cells.
It was only in the mid 1980s that the cloning of the retinoic acid receptors gave a molecular basis to the pleiotropic action of these compound.
Retinoic acid receptors (RARs) and retinoid X receptors (RXRs) are nuclear receptors, like those for steroids or thyroid hormones. They are hormone-activated transcription factors that bind to the promoters of their target genes as RAR/RXR heterodimers and repress or activate their transcription depending on the presence of the hormone.
Both retinoic acid and its three RAR (α, β, γ) receptors have close links to cancer. Retinoids have significant antitumour activities in several clinical settings, in particular in cervical, skin, head and neck cancers, neuroblastoma and oral leukoplakia, where high doses have yielded significant improvements.
A better understanding of the function targeted in the cancer cell and the receptor involved may lead to more specific drugs. Alterations of RARβ expression were reported in a variety of tumors and have suggested that it may act as a tumour suppressor.
The clearest illustration of how alterations in RAR structure are linked to cancer is acute promyelocytic leukemia (APL), where a chromosome translocation fuses the PML gene to that of RARα, creating a PML/RARα fusion protein.
Strikingly, in contrast, the previous malignancies that are RA-responsive, APL cells undergo terminal differentiation ex vivo or in vivo, similar to HL60 or F9 cells. APL therefore became the paradigm for differentiation therapy. Remarkably, APL is also exquisitely sensitive to arsenic trioxide and both RA and arsenic directly target the PML/RARα fusion protein, identifying the first example of oncogene-targeted therapies. Animal models have helped model the effects of these drugs and provide invaluable preclinical systems for one of the best understood malignancies to date.