Retinoic acid inhibits the proliferative response induced by CD40 activation and interleukin-4 in mantle cell lymphoma.
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 [(3)H]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 alpha 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.
Mesh Terms:
Aged, Antigens, CD40, CD40 Ligand, Cell Cycle Proteins, Cell Proliferation, Cell Survival, Cyclin D1, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase Inhibitor p27, Cyclin-Dependent Kinases, Female, Humans, Interleukin-4, Lymphoma, Mantle-Cell, Male, Middle Aged, Proteasome Endopeptidase Complex, Proto-Oncogene Proteins, Receptors, Retinoic Acid, Tretinoin, Tumor Suppressor Proteins
Aged, Antigens, CD40, CD40 Ligand, Cell Cycle Proteins, Cell Proliferation, Cell Survival, Cyclin D1, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase Inhibitor p27, Cyclin-Dependent Kinases, Female, Humans, Interleukin-4, Lymphoma, Mantle-Cell, Male, Middle Aged, Proteasome Endopeptidase Complex, Proto-Oncogene Proteins, Receptors, Retinoic Acid, Tretinoin, Tumor Suppressor Proteins
Cancer Res.
Date: Jan. 15, 2005
PubMed ID: 15695403
View in: Pubmed Google Scholar
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