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

Roberta Cariati, Paola Zancai, Michele Quaia, Giovanna Cutrona, Franca Giannini, Silvana Rizzo, Mauro Boiocchi, Riccardo Dolcetti

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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-lymphoblastaid 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 G0/G1 growth arrest as well as enhancing rates of apoptosis. Conversely, all but I (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 G1-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 G0/G1 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 RARα. The RARα-selective agonist Ro 40-6055 was also effective at very low concentrations (10-10 M). Nevertheless, comparable levels of RARα mRNA were found in RA-responsive and -resistant BL cell lines, indicating that mechanisms different from transcriptional deregulation of RARα probably underlie the differential responsiveness of BL cells. (C) 2000 Wiley-Liss, Inc.

Original languageEnglish
Pages (from-to)375-384
Number of pages10
JournalInternational Journal of Cancer
Volume89
Issue number2
Publication statusPublished - 2000

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myc Genes
Burkitt Lymphoma
Tretinoin
Human Herpesvirus 4
Cell Line
B-Lymphocytes
Growth
Cyclin D3
Isotretinoin
Cell Cycle Proteins
Phosphotransferases
Up-Regulation
Down-Regulation
Apoptosis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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. / Cariati, Roberta; Zancai, Paola; Quaia, Michele; Cutrona, Giovanna; Giannini, Franca; Rizzo, Silvana; Boiocchi, Mauro; Dolcetti, Riccardo.

In: International Journal of Cancer, Vol. 89, No. 2, 2000, p. 375-384.

Research output: Contribution to journalArticle

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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-lymphoblastaid 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 G0/G1 growth arrest as well as enhancing rates of apoptosis. Conversely, all but I (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 G1-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 G0/G1 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 RARα. The RARα-selective agonist Ro 40-6055 was also effective at very low concentrations (10-10 M). Nevertheless, comparable levels of RARα mRNA were found in RA-responsive and -resistant BL cell lines, indicating that mechanisms different from transcriptional deregulation of RARα probably underlie the differential responsiveness of BL cells. (C) 2000 Wiley-Liss, Inc.",
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T1 - 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

AU - Cariati, Roberta

AU - Zancai, Paola

AU - Quaia, Michele

AU - Cutrona, Giovanna

AU - Giannini, Franca

AU - Rizzo, Silvana

AU - Boiocchi, Mauro

AU - Dolcetti, Riccardo

PY - 2000

Y1 - 2000

N2 - 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-lymphoblastaid 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 G0/G1 growth arrest as well as enhancing rates of apoptosis. Conversely, all but I (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 G1-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 G0/G1 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 RARα. The RARα-selective agonist Ro 40-6055 was also effective at very low concentrations (10-10 M). Nevertheless, comparable levels of RARα mRNA were found in RA-responsive and -resistant BL cell lines, indicating that mechanisms different from transcriptional deregulation of RARα probably underlie the differential responsiveness of BL cells. (C) 2000 Wiley-Liss, Inc.

AB - 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-lymphoblastaid 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 G0/G1 growth arrest as well as enhancing rates of apoptosis. Conversely, all but I (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 G1-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 G0/G1 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 RARα. The RARα-selective agonist Ro 40-6055 was also effective at very low concentrations (10-10 M). Nevertheless, comparable levels of RARα mRNA were found in RA-responsive and -resistant BL cell lines, indicating that mechanisms different from transcriptional deregulation of RARα probably underlie the differential responsiveness of BL cells. (C) 2000 Wiley-Liss, Inc.

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