Retinoic acid inhibits the proliferative response induced by CD40 activation and interleukin-4 in mantle cell lymphoma

Massimo Guidoboni, Paola Zancai, Roberta Cariati, Silvana Rizzo, Jessica Dal Col, Alessandro Pavan, Annunziata Gloghini, Michele Spina, Antonio Cuneo, Fabrizio Pomponi, Antonio Bononi, Claudio Doglioni, Roberta Maestro, Antonino Carbone, Mauro Boiocchi, Riccardo Dolcetti

Research output: Contribution to journalArticle

Abstract

Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin's lymphoma with poor response to therapy and unfavorable prognosis. Here, we show that retinoic acid (RA) isomers significantly inhibit the proliferation of both primary MCL cultures (n = 7) and established cell lines (Granta 519 and SP-53) as shown by [ 3H]thymidine uptake and carboxyfluorescein diacetate succinimidyl ester labeling coupled with cyclin D1 staining. RA induces cell accumulation in G 0-G 1 together with a marked up-regulation of p27 Kip1 by inhibiting ubiquitination and proteasome-dependent degradation of the protein. The p21 Cip1 inhibitor was also up-regulated by RA in Granta 519 cells, whereas the expression of cyclin D1 is unaffected. Most of RA-induced p27 Kip1 was bound to cyclin D1/cyclin-dependent kinase 4 complexes, probably contributing to the decreased cyclin-dependent kinase 4 kinase activity and pRb hypophosphorylation observed in RA-treated cells. Experiments with receptor-selective ligands indicate that RA receptor α cooperates with retinoid X receptors in mediating RA-dependent MCL cell growth inhibition. Notably, RA isomers, and particularly 9-cis-RA, also inhibited the growth-promoting effect induced in primary MCL cells by CD40 activation alone or in combination with interleukin-4. Immunohistochemical analysis showed that significant numbers of CD40L-expressing lymphoid cells are present in lymph node biopsies of MCL patients. These results therefore further strengthen the possibility that triggering of CD40 by infiltrating CD40L+ cells may continuously promote the growth of MCL cells in vivo. On these grounds, our findings that RA inhibits basal MCL proliferation as well as MCL growth-promoting effects exerted by microenvironmental factors make these compounds highly attractive in terms of potential clinical efficacy in this setting.

Original languageEnglish
Pages (from-to)587-595
Number of pages9
JournalCancer Research
Volume65
Issue number2
Publication statusPublished - Jan 15 2005

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Guidoboni, M., Zancai, P., Cariati, R., Rizzo, S., Dal Col, J., Pavan, A., Gloghini, A., Spina, M., Cuneo, A., Pomponi, F., Bononi, A., Doglioni, C., Maestro, R., Carbone, A., Boiocchi, M., & Dolcetti, R. (2005). Retinoic acid inhibits the proliferative response induced by CD40 activation and interleukin-4 in mantle cell lymphoma. Cancer Research, 65(2), 587-595.