Retinoid targets in cancer therapy and chemoprevention.
The retinoids are natural and synthetic derivatives of vitamin A. These cancer therapeutic and chemopreventive agents exert anti-proliferative, differentiation-inducing, pro-apoptotic and other biological effects. The retinoids act through nuclear retinoid receptors to activate target genes that signal retinoid biological effects. Direct retinoid targets contain retinoid responsive elements in their promoters, are directly regulated by retinoids and reproduce retinoid biological effects once introduced into a responsive cell context. Through studies conducted in in vitro models, a proteolytic mechanism was linked to retinoid induced tumor cell differentiation and chemopreventive effects. Retinoid treatments can activate the proteasome-dependent degradation pathway. In acute promyelocytic leukemia (APL), all-trans-retinoic acid (RA) can also trigger degradation of the oncogenic protein, PML-RARalpha. Microarray analysis revealed involvement of an E1-like ubiquitin-activating enzyme, UBE1L, in this induction. Retinoid chemopreventive activity in human bronchial epithelial cells was linked to triggering of G(1) cell cycle arrest, concomitant growth suppression, and a decline in expression of G(1) cyclins. This can engage proteasome-dependent cyclin degradation, causing G(1) arrest and this permits repair of genomic DNA damage. The epidermal growth factor receptor (EGFR) was also identified as a retinoid target. Retinoids exert diverse biological effects. Different retinoid target genes likely trigger distinct effects. Identification of target genes is the next step towards a molecular understanding of mechanisms of retinoid response or resistance in cancer therapy and chemoprevention.
D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D018236:Carcinoma, Embryonal / Q000628:therapy; D002454:Cell Differentiation; D018890:Chemoprevention; D002986:Clinical Trials as Topic; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy* / Q000517:prevention & control*; D020411:Oligonucleotide Array Sequence Analysis; D012176:Retinoids / Q000378:metabolism*
D016588:Anticarcinogenic Agents; D012176:Retinoids