Agonists of the retinoic acid- and retinoid X-receptors inhibit hepatocytegrowth factor secretion and expression in U87 human astrocytoma cells

Retinoids participate in the onset of differentiation, apoptosis and the in hibition of growth in a wide variety of normal and cancerous cells. Several recent reports have shown that hepatocyte growth factor (HGF), and its rec eptor, c-Met, are expressed at abnormally high levels in various human mali gnant gliomas and exert a strong proliferative action in an autocrine fashi on. These results, consequently, imply that HGF and its receptor may repres ent a major contributor to the progression of such malignancies. Since astr ocytomas are the most frequently occurring glioma, we have shown here that U87 cells - a well-established, human astrocytoma cell line - express both HGF and c-Met, thereby providing a suitable astrocytic tumor model for stud ying the potential role of HGF, functioning in an autocrine mode, in astroc ytic tumorigenesis. Furthermore, we demonstrated the expression of the reti noic acid receptor (RAR) isoforms, RAR alpha, -beta and -gamma, as well as the retinoid x-receptor (RxR) isoforms, RxR alpha and -beta, by RT-PCR and western blot analysis in these cells. Since ligands of the RARs and RxRs ar e known to exert growth inhibitory effects on various tumor cells which inc lude some astrocytomas, we speculated that such effect of retinoids might b e mediated via inhibition of HGF secretion in human astrocytoma cells. Inde ed, we have shown that the RAR agonists, all-trans retinoic acid (ATRA) and (E)-4-[2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthylenyl)-1-propeny l] benzoic acid (TTNPB), inhibited HGF secretion with half maximal inhibiti on occurring at 3.0 muM and 15 nM, respectively, as did the RxR agonists, 9 -cis- and 13-cis retinoic acid (9cRA and 13cRA, respectively), which exerte d half-maximal inhibitory effects at 40 and 25 nM, respectively. These acti ons of the RAR and RxR agonists appear to be exerted at the transcriptional level as assessed by Northern blot analysis. Taken together, our results s how for the first time that retinoids, acting via the RAR and RxRs, signifi cantly inhibit both the secretion and expression of HGF, thereby interrupti ng a potentially highly tumorigenic autocrine loop in astrocytoma cells. (C ) 2001 Elsevier Science B.V. All rights reserved.