An essential part for Rho–associated kinase in the transcellular invasion of tumor cells (original) (raw)

Nature Medicine volume 5, pages 221–225 (1999)Cite this article

Abstract

Adhesion of tumor cells to host cell layers and subsequent transcellular migration are pivotal steps in cancer invasion and metastasis1,2,3. The small GTPase Rho controls cell adhesion and motility through reorganization of the actin cytoskeleton and regulation of actomyosin contractility4. Cultured rat MM1 hepatoma cells migrate through a mesothelial cell monolayer in vitro in a serum–dependent, Rho–mediated manner5. Among several proteins isolated as putative target molecules of Rho, the ROCK (ROK) family of Rho–associated serine–threonine protein kinases6,7,8 are thought to participate in the induction of focal adhesions and stress fibers in cultured cells9, and to mediate calcium sensitization of smooth muscle contraction by enhancing phosphorylation of the regulatory light chain of myosin10. Transfection of MM1 cells with cDNA encoding a dominant active mutant of ROCK conferred invasive activity independently of serum and Rho. In contrast, expression of a dominant negative, kinase–defective ROCK mutant substantially attenuated the invasive phenotype. A specific ROCK inhibitor (Y–27632; ref. 11) blocked both Rho–mediated activation of actomyosin and invasive activity of these cells. Furthermore, continuous delivery of this inhibitor using osmotic pumps considerably reduced the dissemination of MM1 cells implanted into the peritoneal cavity of syngeneic rats. These results indicate that ROCK plays an essential part in tumor cell invasion, and demonstrate its potential as a therapeutic target for the prevention of cancer invasion and metastasis.

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Acknowledgements

We thank T. Murozono for measuring the Y–27632 concentration. This work was supported in part by Grants–in–Aid for Cancer Research for a new 10–year strategy for cancer control from the Ministry of Health and Welfare of Japan, and for Specially Promoted Research from the Ministry of Education, Science, Sports, and Culture of Japan, as well as by grants from the Yamanouchi Foundation for Research on Metabolic Disease, the Uehara Memorial Foundation, the Naito Foundation, the Ichiro Kanahara Foundation (1997), and the Human Frontier Science Program.

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Authors and Affiliations

  1. Department of Tumor Biology, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1–3–3 Nakamichi, Osaka, 537–8511, Higashinari–ku, Japan
    Kazuyuki Itoh, Kiyoko Yoshioka & Hitoshi Akedo
  2. Discovery Research (Tokyo), Yoshitomi Pharmaceutical Industries Ltd., Saitama, 358–0026, Japan
    Masayoshi Uehata
  3. Department of Pharmacology, Faculty of Medicine, Kyoto University, Kyoto, 606–8315, Japan
    Toshimasa Ishizaki & Shuh Narumiya

Authors

  1. Kazuyuki Itoh
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  2. Kiyoko Yoshioka
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  3. Hitoshi Akedo
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  4. Masayoshi Uehata
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  5. Toshimasa Ishizaki
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  6. Shuh Narumiya
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Corresponding author

Correspondence toKazuyuki Itoh.

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Itoh, K., Yoshioka, K., Akedo, H. et al. An essential part for Rho–associated kinase in the transcellular invasion of tumor cells.Nat Med 5, 221–225 (1999). https://doi.org/10.1038/5587

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