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1.
Exp. mol. med ; Exp. mol. med;: e47-2013.
Article de Anglais | WPRIM | ID: wpr-223715

RÉSUMÉ

Here, we report that B-cell lymphoma 2 (Bcl-2) is a novel target molecule of aspirin in breast cancer cells. Aspirin influenced the formation of a complex by Bcl-2 and FKBP38 and induced the nuclear translocation of Bcl-2 and its phosphorylation. These events inhibited cancer cell proliferation and subsequently enhanced MCF-7 breast cancer cell apoptosis. Bcl-2 knockdown using small interfering RNA (siRNA) delayed apoptotic cell death, which correlated with increased proliferation following aspirin exposure. In contrast, Bcl-2 overexpression enhanced the onset of aspirin-induced apoptosis, which was also associated with a significant increase in Bcl-2 phosphorylation in the nucleus. Therefore, this study may provide novel insight into the molecular mechanism of aspirin, particularly its anticancer effects in Bcl-2- and estrogen receptor-positive breast cancer cells.


Sujet(s)
Humains , Transport nucléaire actif/effets des médicaments et des substances chimiques , Apoptose , Acide acétylsalicylique/pharmacologie , Noyau de la cellule/métabolisme , Cellules MCF-7 , Phosphorylation , Liaison aux protéines , Protéines proto-oncogènes c-bcl-2/génétique , Protéines de liaison au tacrolimus/métabolisme
2.
Exp. mol. med ; Exp. mol. med;: 35-42, 2008.
Article de Anglais | WPRIM | ID: wpr-219395

RÉSUMÉ

In order to develop an anti-human TNF-alpha mAb, mice were immunized with recombinant human TNF-alpha. A murine mAb, TSK114, which showed the highest binding activity for human TNF-alpha was selected and characterized. TSK114 specifically bound to human TNF-alpha without cross-reactivity with the homologous murine TNF-alpha and human TNF-beta TSK114 was found to be of IgG1 isotype with kappa light chain. The nucleotide sequences of the variable regions of TSK114 heavy and light chains were determined and analyzed for the usage of gene families for the variable (V), diversity (D), and joining (J) segments. Kinetic analysis of TSK114 binding to human TNF-alpha by surface plasmon resonance technique revealed a binding affinity (KD) of ~5.3 pM, which is about 1,000- and 100-fold higher than those of clinically relevant infliximab (Remicade) and adalimumab (Humira) mAbs, respectively. TSK114 neutralized human TNF-alpha-mediated cytotoxicity in proportion to the concentration, exhibiting about 4-fold greater efficiency than those of infliximab and adalimumab in WEHI 164 cells used as an in vitro model system. These results suggest that TSK114 has the potential to be developed into a therapeutic TNF-alpha-neutralizing antibody with picomolar affinity.


Sujet(s)
Animaux , Humains , Souris , Séquence d'acides aminés , Anticorps monoclonaux/composition chimique , Affinité des anticorps/immunologie , Spécificité des anticorps , Séquence nucléotidique , Technique de Western , Lignée cellulaire , Cytotoxicité immunologique , Test ELISA , Région variable d'immunoglobuline/génétique , Cinétique , Souris de lignée BALB C , Données de séquences moléculaires , Tests de neutralisation , Analyse de séquence de protéine , Facteur de nécrose tumorale alpha/immunologie
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