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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

Authors' Affiliations: ¹ Division of Clinical Immunology, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo; ² Department of Urology, Tokyo Medical College, Tokyo, Japan; ³ Department of Urology, Osaka Medical College, Osaka, Japan; and ⁴ Department of Hematologic Malignancies, Nevada Cancer Institute, Las Vegas, Nevada

Requests for reprints: Chikao Morimoto, Division of Clinical Immunology, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. Phone: 81-3-5449-5549; Fax: 81-3-5449-5548; E-mail: morimoto{at}ims.u-tokyo.ac.jp.

Purpose: 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.

Experimental Design: 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.

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				T. Inamoto, T. Yamada, K. Ohnuma, S. Kina, N. Takahashi, T. Yamochi, S. Inamoto, Y. Katsuoka, O. Hosono, H. Tanaka, et al. Humanized Anti-CD26 Monoclonal Antibody as a Treatment for Malignant Mesothelioma Tumors Clin. Cancer Res., July 15, 2007; 13(14): 4191 - 4200. [Abstract] [Full Text] [PDF]