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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Fidler, I. J. Cancer metastasis. Br. Med. Bull. 47, 157–177 (1991).
Nicolson, G.L. et al. Adhesive, invasive, and growth properties of selected metastatic variants of a murine large–cell lymphoma. Invasion Metastasis 9, 102–116 (1989).
Liotta, L.A., Steeg, P.S. & Stetler–Stevenson, W.G. Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell 64, 327–336 (1991).
Chrzanowska–Wodnicka, M. & Burridge, K. Rho–stimulated contractility drives the formation of stress fibers and focal adhesions. J. Cell Biol. 133, 1403–1415 (1996).
Yoshioka, K., Matsumura, F., Akedo, H. & Itoh, K. Small GTP–binding protein Rho stimulates the actomyosin system, leading to invasion of tumor cells J. Biol. Chem. 273, 5146– 5154 (1998).
Leung, T., Manser, E., Tan, L. & Lim, L. A novel serine/threonine kinase binding the Ras–related RhoA GTPase which translocates the kinase to peripheral membranes. J. Biol. Chem. 270, 29051–29054 (1995).
Ishizaki, T. et al. The small GTP–binding protein Rho binds to and activates a 160 kDa Ser/Thr protein kinase homologous to myotonic dystrophy kinase. EMBO J. 15, 1885–1893 (1996).
Matsui, T. et al. Rho–associated kinase, a novel serine/threonine kinase, as a putative target for the small GTP binding protein Rho. EMBO J. 15, 2208–2216 (1996).
Ishizaki, T. et al. p160ROCK, a Rho–associated coiled coil forming protein kinase, works downstream of Rho and induces focal adhesions. FEBS Lett. 404, 118–124 (1997).
Amano, M. et al. Phosphorylation and activation of myosin by Rho–associated kinase (Rho–kinase). J. Biol. Chem. 271, 20246–20249 (1996).
Uehata, M. et al. A key role for p160ROCK–mediated Ca++ sensitization of smooth muscle in hypertension. Nature 389, 990–994 (1997).
Sekine, A., Fujiwara, M. & Narumiya, S. Asparagine residue in the rho gene product is the modification site for Botulinum ADP–ribosyltransferase. J. Biol. Chem. 264, 8602–8605 (1989).
Sahai, E., Alberts, A. S. & Treisman, R. RhoA effector mutants reveal distinct effector pathway for cytoskeletal reorganization, SRF activation and transformation. EMBO J. 17, 1350–1361 (1998).
Matsumura, F., Ono, S., Yamakita, Y., Totsukawa, G. & Yamashiro, S. Specific localization of serine 19 phosphorylated myosin II during cell locomotion and mitosis of cultured cells. J. Cell Biol. 140, 119–129 (1998).
Vleminckx, K., Vakaet, L., Mareel, M., Fiers, W. & Van Roy, F. Genetic manipulation of E–cadherin expression by epithelial tumor cells reveals an invasion suppressor role. Cell 66, 107–119 (1991).
Perl, A., Wilgenbus, P., Dahl, U., Semb, H. & Christofori, G. A causal role for E–cadherin in the transition from adenoma to carcinoma. Nature 392, 190–193 (1998).
Bafetti, L., Young, N., Itoh, Y. & Stack, M. S. Intact vitronectin induces matrix metalloproteinase–2 and tissue inhibitor of metalloproteinase–2 expression and enhanced cellular invasion by melanoma cells. J. Biol. Chem. 273, 143–149 (1998).
Talbot, D. C. & Brown, P. D. Experimental and clinical studies on the use of matrix metalloproteinase inhibitors for the treatment of cancer. Eur. J. Cancer 32, 2528– 2533 (1996).
Narumiya, S. The small GTPase Rho: cellular functions and signal transduction. J. Biochem. (Tokyo) 120, 215–228 (1996).
Madaule, P. et al. Role of citron kinase as a target of the small GTPase Rho in cytokinesis. Nature 394, 491– 494 (1998).
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.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/5587
This article is cited by
-
Discovery of a signaling feedback circuit that defines interferon responses in myeloproliferative neoplasms
Nature Communications (2022)
-
Synthesis, Characterization and Employed Doxycycline Capped Gold Nanoparticles on TRP Channel Expressions in SKBR3 Breast Cancer Cells and Antimicrobial Activity
Journal of Cluster Science (2022)
-
Targeting the cytoskeleton against metastatic dissemination
Cancer and Metastasis Reviews (2021)
-
Statin inhibits large hepatitis delta antigen-Smad3 -twist-mediated epithelial-to-mesenchymal transition and hepatitis D virus secretion
Journal of Biomedical Science (2020)
-
Celastrol inhibits ezrin-mediated migration of hepatocellular carcinoma cells
Scientific Reports (2020)