Anti-CD26 monoclonal antibody-mediated G1-S arrest of human renal clear cell carcinoma Caki-2 is associated with retinoblastoma substrate dephosphorylation, cyclin-dependent kinase 2 reduction, p27(kip1) enhancement, and disruption of binding to the extracellular matrix.
OBJECTIVE
CD26 is a 110-kDa cell surface glycoprotein with a role in tumor development through its association with key intracellular proteins. In this report, we show that binding of soluble anti-CD26 monoclonal antibody (mAb) inhibits the growth of the human renal carcinoma cells in both in vitro and in vivo experiments.


METHODS
Growth inhibition by anti-CD26 mAb was assessed using proliferation assay and cell cycle analysis. Anti-CD26 mAb, chemical inhibitors, dominant-negative, or constitutively active forms of specific signaling molecules were used to evaluate CD26-associated pathways. The in vivo growth-inhibitory effect of anti-CD26 mAb was also assessed in a human renal carcinoma mouse xenograft model.


RESULTS
In vitro experiments show that anti-CD26 mAb induces G1-S cell cycle arrest associated with enhanced p27(kip1) expression, down-regulation of cyclin-dependent kinase 2, and dephosphorylation of retinoblastoma substrate. Moreover, our data show that enhanced p27(kip1) expression is dependent on the attenuation of Akt activity. Anti-CD26 mAb also internalizes cell surface CD26, leading to decreased binding to collagen and fibronectin. Experiments with a mouse xenograft model involving human renal carcinoma cells show that anti-CD26 mAb treatment drastically inhibits tumor growth in tumor-bearing mice, resulting in enhanced survival.


CONCLUSIONS
Taken together, our data strongly suggest that anti-CD26 mAb treatment may have potential clinical use for CD26-positive renal cell carcinomas.
Inamoto
Teruo
T
Division of Clinical Immunology, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Japan.
Yamochi
Tadanori
T
Ohnuma
Kei
K
Iwata
Satoshi
S
Kina
Shinichiro
S
Inamoto
Sakiko
S
Tachibana
Masaaki
M
Katsuoka
Yoji
Y
Dang
Nam H
NH
Morimoto
Chikao
C
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D000937:Antigen-Antibody Reactions; D001665:Binding Sites; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis / Q000378:metabolism*; D018819:Dipeptidyl Peptidase 4 / Q000096:biosynthesis / Q000276:immunology; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010766:Phosphorylation / Q000187:drug effects; D016160:Retinoblastoma Protein / Q000378:metabolism*; D016196:S Phase / Q000187:drug effects; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D054873:Dipeptidyl-Peptidase IV Inhibitors; D016160:Retinoblastoma Protein; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051357:Cyclin-Dependent Kinase 2; D018819:Dipeptidyl Peptidase 4