title: Retinoic acid induces persistent, RARalpha-mediated anti-proliferative responses in Epstein-Barr virus-immortalized b lymphoblasts carrying an activated C-MYC oncogene but not in Burkitt's lymphoma cell lines.
abstract: We have previously demonstrated that 13-cis-retinoic acid (RA), 9-cis-RA and all-trans-RA (ATRA) powerfully inhibit the proliferation of Epstein-Barr virus-immortalized B-lymphoblastoid cell lines (LCLs). The aim of the present study was to assess whether these compounds are effective at inhibiting the growth of B cells at more advanced stages of lymphomagenesis, including fully transformed B lymphocytes. To this end, c-myc-transfected LCLs (myc-LCLs) and Burkitt's lymphoma (BL) cell lines were used. We report that 13-cis-RA, 9-cis-RA and ATRA also markedly inhibit the proliferation of myc-LCLs by inducing G(0)/G(1) growth arrest as well as enhancing rates of apoptosis. Conversely, all but 1 (DG75) of the 8 BL cell lines investigated were poorly RA-responsive. Moreover, unlike LCLs and myc-LCLs, RA-treated DG75 cells rapidly resumed proliferation upon drug removal. Analysis of cell cycle-regulatory proteins showed that, as in LCLs, strong up-regulation of p27(Kip-1) and increased levels of under-phosphorylated pRb and p130 were detected in RA-treated DG75 cells. While the catalytic activity of all 3 G(1)-associated CDKs (CDK2, CDK4 and CDK6) was strongly inhibited in RA-treated LCLs, only CDK2-associated kinase activity was reduced in DG75 cells arrested in G(0)/G(1) by RA. Moreover, RA-treated DG75 cells failed to show the down-regulation of cyclin D3 observed in LCLs. Use of receptor-selective agonists and antagonists showed that in LCLs and RA-responsive BL cells, RA-induced growth arrest is mainly mediated by RARalpha. The RARalpha-selective agonist Ro 40-6055 was also effective at very low concentrations (10(-10) M). Nevertheless, comparable levels of RARalpha mRNA were found in RA-responsive and -resistant BL cell lines, indicating that mechanisms different from transcriptional deregulation of RARalpha probably underlie the differential responsiveness of BL cells.
authors.affiliation: Division of Experimental Oncology 1, Centro di Riferimento Oncologico, Aviano, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Cariati
authors.forename: P
authors.initials: P
authors.lastname: Zancai
authors.forename: M
authors.initials: M
authors.lastname: Quaia
authors.forename: G
authors.initials: G
authors.lastname: Cutrona
authors.forename: F
authors.initials: F
authors.lastname: Giannini
authors.forename: S
authors.initials: S
authors.lastname: Rizzo
authors.forename: M
authors.initials: M
authors.lastname: Boiocchi
authors.forename: R
authors.initials: R
authors.lastname: Dolcetti
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D002051:Burkitt Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral; D018014:Gene Transfer Techniques; D016259:Genes, myc; D004854:Herpesvirus 4, Human; D006801:Humans; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D015398:Signal Transduction / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D016271:Proto-Oncogene Proteins c-myc; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin