Monoclonal antibody (mAb)-induced down-regulation of RON receptor tyrosine kinase diminishes tumorigenic activities of colon cancer cells

  • Authors:
    • Zhuzhu Li
    • Hangping Yao
    • Sunny Guin
    • Snehal S. Padhye
    • Yong-Qing Zhou
    • Ming-Hai Wang
  • View Affiliations

  • Published online on: Sunday, August 1, 2010
  • Pages: 473-482 DOI: 10.3892/ijo_00000696
0

Abstract

Overexpression of the RON receptor tyrosine kinase contributes to pathogenesis of epithelial cancers and disruption of RON signals has potential for therapeutic intervention. Here, we report the inhibitory effects of monoclonal antibodies (Zt/g4, Zt/f2 and Zt/c9) on RON expression and tumorigenic activities in colon cancer cells. Persistent treatment of colon SW620 or other cells with Zt/g4 dramatically down-regulated RON expression as evident by Western blot and cell surface fluorescent analyses. The effect was both concentration and time-dependent and specific to RON but not to structure-related MET or -unrelated EGFR. The cause of reduction was antibody-induced receptor internalization followed by protein degradation through lysosome and proteasome-mediated pathways. Down-regulation of RON impaired intracellular signaling events. Phosphorylation of Erk1/2 and AKT was dramatically reduced after Zt/g4 treatment. Zt/g4 treatment also affects activities of DVL and GSK-3β, which results in diminished β-catenin nuclear translocation. Functional studies revealed that Zt/g4 treatment changes cellular morphology and affects colony formation in soft agar. It also increased the sensitivity of SW620 cells in response to gemcitabine-induced cytotoxicity. In this case, the death of SW620 cells was significantly increased when Zt/g4 was used in combination with gemcitabine. We conclude that persistent treatment of cancer cells with antibodies specific to RON extracellular domains results in down-regulation of RON expression. The reduced RON expression is accompanied with impaired signaling events, diminished tumorigenic activities and enhanced sensitivity towards cytotoxic drugs. Thus, Zt/g4-directed targeting could have therapeutic implication for controlling tumorigenic phenotypes of cancer cells.

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August 2010
Volume 37 Issue 2

Print ISSN: 1019-6439
Online ISSN:1791-2423

2015 Impact Factor: 3.018
Ranked #30/211 Oncology
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APA
Li, Z., Yao, H., Guin, S., Padhye, S.S., Zhou, Y., & Wang, M. (2010). Monoclonal antibody (mAb)-induced down-regulation of RON receptor tyrosine kinase diminishes tumorigenic activities of colon cancer cells. International Journal of Oncology, 37, 473-482. http://dx.doi.org/10.3892/ijo_00000696
MLA
Li, Z., Yao, H., Guin, S., Padhye, S. S., Zhou, Y., Wang, M."Monoclonal antibody (mAb)-induced down-regulation of RON receptor tyrosine kinase diminishes tumorigenic activities of colon cancer cells". International Journal of Oncology 37.2 (2010): 473-482.
Chicago
Li, Z., Yao, H., Guin, S., Padhye, S. S., Zhou, Y., Wang, M."Monoclonal antibody (mAb)-induced down-regulation of RON receptor tyrosine kinase diminishes tumorigenic activities of colon cancer cells". International Journal of Oncology 37, no. 2 (2010): 473-482. http://dx.doi.org/10.3892/ijo_00000696