A modified version of galectin-9 induces cell cycle arrest and apoptosis of Burkitt and Hodgkin lymphoma cells.
The identification of galectin-9 as a ligand for T-cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3), expressed on T-helper type-1 (Th1) cells, has established the Tim-3-galectin-9 pathway as a regulator of Th1 immunity. Whereas there is compelling evidence for the effects of galectin-9 on T-cell fate, limited information is available on the impact of galectin-9 on B lymphocytes. We found that protease-resistant galectin-9, hG9NC(null), but not galectin-1 or -8, prevented cell growth of malignant B cells, such as Burkitt lymphoma (BL) and Hodgkin lymphoma (HL). beta-galactoside binding was essential for galectin-9-induced cell growth suppression. hG9NC(null) induced cell cycle arrest by reducing the expression of cyclin D1, D2, B1, Cdk4, Cdc25C and c-Myc, and apoptosis by reducing the expression of XIAP, c-IAP2 and survivin. Most of the genes that encode these proteins are regulated by nuclear factor-kappaB (NF-kappaB), and constitutive activation of NF-kappaBeta is a common characteristic of both types of malignancies. hG9NC(null) inhibited IkappaBalpha phosphorylation, resulting in suppression of NF-kappaB. AP-1 has also been implicated in the control of cell survival. hG9NC(null) inhibited the expression of JunD, resulting in the suppression of AP-1. Our results suggest that hG9NC(null) is a potentially suitable agent for the management of BL and HL.
Makishi
Shoko
S
Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan.
Okudaira
Taeko
T
Ishikawa
Chie
C
Sawada
Shigeki
S
Watanabe
Toshiki
T
Hirashima
Mitsuomi
M
Sunakawa
Hajime
H
Mori
Naoki
N
D017209:Apoptosis / Q000187:drug effects*; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D002051:Burkitt Lymphoma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D020169:Caspases / Q000032:analysis; D002453:Cell Cycle / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor / Q000166:cytology / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D037161:Galectins / Q000494:pharmacology*; D006689:Hodgkin Disease / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D006801:Humans; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction
D037161:Galectins; C105032:LGALS9 protein, human; D016328:NF-kappa B; D020169:Caspases