Stromelysin-3 induction and interstitial collagenase repression by retinoic acid. Therapeutical implication of receptor-selective retinoids dissociating transactivation and AP-1-mediated transrepression.
Human stromelysin-3 and interstitial collagenase are matrix metalloproteinases whose expression by stromal cells in several types of carcinomas has been associated with cancer progression. We compared here the regulation of the expression of both proteinases by retinoids in human fibroblasts. Physiological concentrations of retinoic acid were found to simultaneously induce stromelysin-3 and repress interstitial collagenase. In both cases, the involvement of a transcriptional mechanism was supported by run-on assays. Furthermore, in transient transfection experiments, the activity of the stromelysin-3 promoter was induced by retinoic acid through endogenous receptors acting on a DR1 retinoic acid-responsive element. The ligand-dependent activation of the receptors was also investigated by using selective synthetic retinoids, and we demonstrated that retinoic acid-retinoid X receptor heterodimers were the most potent functional units controlling both stromelysin-3 induction and interstitial collagenase repression. However, specific retinoids dissociating the transactivation and the AP-1-mediated transrepression functions of the receptors were found to repress interstitial collagenase without inducing stromelysin-3. These findings indicate that such retinoids may represent efficient inhibitors of matrix metalloproteinase expression in the treatment of human carcinomas.
Guérin
E
E
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Université Louis Pasteur, BP 163, 67404 Illkirch cedex, France.
Ludwig
M G
MG
Basset
P
P
Anglard
P
P
D002277:Carcinoma / Q000188:drug therapy; D017364:Collagenases / Q000096:biosynthesis* / Q000235:genetics; D004357:Drug Synergism; D004794:Enzyme Repression; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D020781:Matrix Metalloproteinase 1; D053507:Matrix Metalloproteinase 11; D008666:Metalloendopeptidases / Q000096:biosynthesis* / Q000235:genetics; D011401:Promoter Regions, Genetic; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D012208:Rhabdomyosarcoma; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015533:Transcriptional Activation; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D018168:Receptors, Retinoic Acid; D018808:Transcription Factor AP-1; D014212:Tretinoin; D017364:Collagenases; D053507:Matrix Metalloproteinase 11; D008666:Metalloendopeptidases; D020781:Matrix Metalloproteinase 1