THE PROMISE OF RETINOIDS TO FIGHT AGAINST CANCER
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© 2001 Macmillan Magazines Ltd REVIEWS Multicellular organisms require specific mechanisms of intercellular communication to organize their complex body plan during embryogenesis, and to maintain the physiological functions of each organ throughout life. Retinoic acids (RAs) are signalling molecules that, together with their nuclear retinoid (RARα, β and γ) and rexinoid (RXRα, β and γ) receptors, establish genetic communication networks that are essential for embryonic development 1. But they also have important physiological functions, particularly in the brain 2,3 and reproductive 4 system, by regulating organogenesis 5 , organ homeostasis 6,7 , and cell growth, differentiation and death 8,9 . RARs and RXRs are transcription factors that act mainly, if not exclusively, as RAR–RXR heterodimers 10 . These heterodimers have two distinct functions: first, they modulate the frequency of transcription initiation of target genes after binding to RA response elements (RAREs) in their promoters; and second, they affect the efficiency of other signalling pathways (‘crosstalk’) by mechanisms that remain elusive. This crosstalk indicates that retinoid receptors can be targets of other pathways. A well-established example is the mutual repression of transcriptional activation that is mediated by the AP1 (c-JUN–c-FOS) transcription factor and RARs 11 . Retinoids are both our friends and our foes. The pleiotropic actions and their power to drive cells into differentiation and death offer great promise for can- cer therapy, and the beneficial effects of retinoid- based ‘differentiation therapy’ have been impressively shown in the case of ACUTE PROMYELOCYTIC LEUKAEMIA (APL). But RAs are also powerful TERATOGENS and, just like the sorcerer’s apprentice, we have to learn more about their function before we can fully exploit these powerful substances. Origin of retinoids Dietary-derived all-trans RA (ATRA) is the main sig- nalling retinoid in the body (BOX 1), and mediates its action through RAR–RXR heterodimers. Although 9-cis RA has been detected in humans 12 , it remains to be shown that this isomer corresponds to a bona fide ligand for RARs and RXRs. Other physiological metabolites of vitamin A in humans include 1,4-hydroxy-4,14-retro- retinol; its function in regulating cell proliferation has been recognized since 1991 (REF. 13), but its mechanism of action is still unclear. Numerous synthetic retinoids are now available for experimental exploitation. Some of these compounds were generated with the aim of finding selective ago- nists and antagonists for each of the six receptors, which are known from gene-ablation studies to have distinct — albeit potentially redundant — functionali- ties. So, for nearly every receptor isotype, selective ago- nists or antagonists exist and several three-dimensional structures of RAR and RXR ligand-binding domain (LBD) monomers and heterodimers, some bound to agonists and antagonists, have been solved 14 . Furthermore, ligands can be synthesized that selectively activate a subset of the functions of the natural ligands. For example, ATRA can repress AP1-mediated sig- nalling as well as directly activating RAR–RXR target genes, but ligands have been generated that perform only one of these functions 11 . THE PROMISE OF RETINOIDS TO FIGHT AGAINST CANCER Lucia Altucci* ‡ and Hinrich Gronemeyer ‡ Retinoids have a reputation for being both detrimental and beneficial: they are teratogens, but they also have tumour-suppressive capacity. Cell biology and genetics have significantly improved our understanding of the mechanisms that underlie the anti-proliferative action of retinoids. Recent elucidation of the pathways that are activated by retinoids will help us to exploit the beneficial aspects of this powerful class of compounds for cancer therapy and prevention. AP1 A transcription factor that is composed of c-JUN, either as a homodimer or as a heterodimer with c-FOS. Both are ‘immediate-early genes’: expression of these genes is low or undetectable in quiescent cells, but is activated within minutes after extracellular stimulation, such as addition of a growth factor. NATURE REVIEWS | CANCER VOLUME 1 | DECEMBER 2001 | 181 *Dipartimento di Patologia Generale e Oncologia, Seconda Università degli Studi di Napoli, via L. de Crecchio, Napoli 80138, Italy. ‡ Institut de Génétique et de Biologie Moléculaire et Cellulaire, (IGBMC)/CNRS/INSERM/ ULP, BP 163, 67404 Illkirch Cedex, C. U. de Strasbourg, France. e-mails: [email protected], [email protected]
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Transcript of THE PROMISE OF RETINOIDS TO FIGHT AGAINST CANCER
© 2001 Macmillan Magazines Ltd
© 2001 Macmillan Magazines Ltd
© 2001 Macmillan Magazines Ltd
© 2001 Macmillan Magazines Ltd
© 2001 Macmillan Magazines Ltd
© 2001 Macmillan Magazines Ltd
© 2001 Macmillan Magazines Ltd
© 2001 Macmillan Magazines Ltd
© 2001 Macmillan Magazines Ltd
© 2001 Macmillan Magazines Ltd
© 2001 Macmillan Magazines Ltd
© 2001 Macmillan Magazines Ltd
© 2001 Macmillan Magazines Ltd
