Retinoic acid induces persistent, RARα-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
✍ Scribed by Roberta Cariati; Paola Zancai; Michele Quaia; Giovanna Cutrona; Franca Giannini; Silvana Rizzo; Mauro Boiocchi; Riccardo Dolcetti
- Publisher
- John Wiley and Sons
- Year
- 2000
- Tongue
- French
- Weight
- 260 KB
- Volume
- 86
- Category
- Article
- ISSN
- 0020-7136
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✦ Synopsis
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 RAresponsive. Moreover, unlike LCLs and myc-LCLs, RAtreated 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 RAR␣. The RAR␣-selective agonist Ro 40-6055 was also effective at very low concentrations (10 -10 M). Nevertheless, comparable levels of RAR␣ mRNA were found in RA-responsive and -resistant BL cell lines, indicating that mechanisms different from transcriptional deregulation of RAR␣ probably underlie the differential responsiveness of BL cells.