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.
Guidoboni
Massimo
M
Immunovirology and Biotherapy Unit, Department of Pre-Clinical and Epidemiological Research, IRCCS-National Cancer Institute, Aviano (PN), Italy.
Zancai
Paola
P
Cariati
Roberta
R
Rizzo
Silvana
S
Dal Col
Jessica
J
Pavan
Alessandro
A
Gloghini
Annunziata
A
Spina
Michele
M
Cuneo
Antonio
A
Pomponi
Fabrizio
F
Bononi
Antonio
A
Doglioni
Claudio
C
Maestro
Roberta
R
Carbone
Antonino
A
Boiocchi
Mauro
M
Dolcetti
Riccardo
R
D000368:Aged; D019013:CD40 Antigens / Q000494:pharmacology*; D023201:CD40 Ligand / Q000096:biosynthesis; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology*; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000502:physiology; D014212:Tretinoin / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D019013:CD40 Antigens; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D061988:Proteasome Inhibitors; D011518:Proto-Oncogene Proteins; D018168:Receptors, Retinoic Acid; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; D023201:CD40 Ligand; D050760:Cyclin-Dependent Kinase Inhibitor p27; D015847:Interleukin-4; D014212:Tretinoin; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D046988:Proteasome Endopeptidase Complex