Antitumor effect of beta2-microglobulin in leukemic cell-bearing mice via apoptosis-inducing activity: activation of caspase-3 and nuclear factor-kappaB.
We have reported previously that beta2-microglobulin (beta2m) induces apoptosis in leukemic cells in vitro, and that an interaction between beta2m and HLA class I antigen induces apoptosis. Here we examined whether beta2m can induce apoptosis in leukemic cells in vivo and whether it has an antitumor effect in tumor-bearing mice. Daily administration of 50 or 250 microg of beta2m induced apoptosis and an antitumor effect on K562 leukemia cell-bearing mice in the same manner as tumor necrosis factor-alpha. In tumor tissues in beta2m-treated mice, both caspase-3 and nuclear factor-kappaB (NF-kappaB) were stained more strongly than in control mice by anti-caspase-3 and anti-NF-kappaB p65/Rel A polyclonal antibodies. We also observed the in vivo immunological effects of beta2m on lymphoid and hematopoietic organs, such as thymus, bone marrow, Peyer's patches, liver, and spleen in normal mice. Using antibodies against caspase-3 and NF-kappaB, immunohistochemical staining showed that no specific tissues were damaged or stained in normal mice. We conclude that beta2m stimulates caspase-3 and NF-kappaB pathways to induce apoptosis, making it a useful approach to a new therapy for leukemia.
Mori
M
M
Department of Hematology, Jichi Medical School, Tochigi 329-04, Japan.
Terui
Y
Y
Tanaka
M
M
Tomizuka
H
H
Mishima
Y
Y
Ikeda
M
M
Kasahara
T
T
Uwai
M
M
Ueda
M
M
Inoue
R
R
Itoh
T
T
Yamada
M
M
Hayasawa
H
H
Furukawa
Y
Y
Ishizaka
Y
Y
Ozawa
K
K
Hatake
K
K
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000096:biosynthesis / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D004789:Enzyme Activation; D018922:HL-60 Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D020287:In Situ Nick-End Labeling; D020014:K562 Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016328:NF-kappa B / Q000096:biosynthesis*; D011994:Recombinant Proteins / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D001613:beta 2-Microglobulin / Q000276:immunology / Q000494:pharmacology*
D016328:NF-kappa B; D011994:Recombinant Proteins; D001613:beta 2-Microglobulin; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases