Abstract
It is projected that in 2005, approximately 220 900 men will be newly diagnosed with carcinoma of the prostate (CaP). Men who are diagnosed with locally advanced or metastatic disease undergo androgen ablation therapy and most will relapse and progress within 18 months. Metastasis to bone is the major clinical concern during CaP progression, as it is associated with intractable pain, bone fracture and paralysis resulting from spinal cord compression. Therefore, an understanding of the key mechanisms involved in CaP cell bone metastasis is vital to development of novel treatments. The Rho GTPases are molecular switches involved in cell survival, motility and invasion. Increased expression of RhoC GTPase is linked to enhanced metastatic potential in multiple cancers; however, the role of RhoC GTPase in CaP metastasis has not been addressed. In the current study, we demonstrate that RhoC GTPase is expressed and active in PC-3 CaP cells. RhoC inhibition, either pharmacologically with C3 exotransferase or molecularly through expression of a dominant-negative RhoC, promotes IGF-I stimulated random motility but decreases in vitro invasion and experimental metastases. Inhibition of RhoC activity results in drastic morphologic changes and alterations in the expression and distribution of focal adhesion-related proteins. These data suggest that RhoC inhibition leads to activation of other GTPases involved in nondirected motility and that expression of active RhoC is required for the invasive phenotype of PC-3 cells.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Abbreviations
- CaP:
-
prostate cancer
- Rho:
-
Ras homology
- IGF-I:
-
insulin-like growth factor I
- col I:
-
collagen type I
- FAK:
-
focal adhesion kinase
- PKL:
-
paxillin kinase linker
- EMT:
-
epithelial to mesenchymal transition
- SEM:
-
scanning electron microscopy
References
Abate-Shen C, Shen MM . (2000). Genes Dev 14: 2410–2434.
Aktories K, Hall A . (1989). Trends Pharmacol Sci 10: 415–418.
Aktories K, Braun U, Rosener S, Just I, Hall A . (1989). Biochem Biophys Res Commun 158: 209–213.
Aktories K . (1997). Trends Microbiol 5: 282–288.
Albrecht-Buehler G . (1977). Cell 11: 395–404.
Alcover J, Fernandez-Conde M, Carrere W, Serrallach M, Carretero P . (1994). Actas Urol Esp 18 (Suppl): 409–416.
American Cancer Society Facts and Figures (2005).
Bockhorn M, Roberge S, Sousa C, Jain RK, Munn LL . (2004). Cancer Res 64: 2469–2473.
Cancer Management: A Multidisciplinary Approach (1999) 3rd ed.
Carr KM, Bittner M, Trent JM . (2003). Oncogene 22: 3076–3080.
Chang F, Steelman LS, Shelton JG, Lee JT, Navolanic PM, Blalock WL et al. (2003). Int J Oncol 22: 469–480.
Chung LW, Baseman A, Assikis V, Zhau HE . (2005). J Urol 173: 10–20.
Clark EA, Golub TR, Lander ES, Hynes RO . (2000). Nature 406: 532–535.
Cooper CR, Pienta KJ . (2000). Prostate Cancer Prostatic Dis 3: 6–12.
Danen EH, Sonneveld P, Sonnenberg A, Yamada KM . (2000). J Cell Biol 151: 1413–1422.
del Peso L, Hernandez-Alcoceba R, Embade N, Carnero A, Esteve P, Paje C et al. (1997). Oncogene 15: 3047–3057.
Diekmann D, Hall A . (1995). Meth Enzymol 256: 207–215.
Edlund S, Landstrom M, Heldin CH, Aspenstrom P . (2002). Mol Biol Cell 13: 902–914.
Evers EE, van der Kammen RA, ten Klooster JP, Collard JG . (2000). Meth Enzymol 325: 403–415.
Fritz G, Just I, Kaina B . (1999). Int J Cancer 81: 682–687.
Garber K . (2005). J Natl Cancer Inst 97: 790–792.
Geyer M, Wittinghofer A . (1997). Curr Opin Struct Biol 7: 786–792.
Greenberg DL, Mize GJ, Takayama TK . (2003). Biochemistry 42: 702–709.
Hall A . (1990). Science 249: 635–640.
Hall A . (1998). Science 279: 509–514.
Hellawell GO, Turner GD, Davies DR, Poulsom R, Brewster SF, Macaulay VM . (2002). Cancer Res 62: 2942–2950.
Hendrix MJ, Seftor EA, Seftor RE, Fidler IJ . (1987). Cancer Lett 38: 137–147.
Hodge JC, Bub J, Kaul S, Kajdacsy-Balla A, Lindholm PF . (2003). Cancer Res 63: 1359–1364.
Horiuchi A, Imai T, Wang C, Ohira S, Feng Y, Nikaido T et al. (2003). Lab Invest 83: 861–870.
Imamura F, Mukai M, Ayaki M, Takemura K, Horai T, Shinkai K et al. (1999). Clin Exp Metast 17: 141–148.
Iwamura M, Sluss PM, Casamento JB, Cockett AT . (1993). Prostate 22: 243–252.
Jackson JG, Zhang X, Yoneda T, Yee D . (2001). Oncogene 20: 7318–7325.
Jaffe AB, Hall A . (2002). Adv Cancer Res 84: 57–80.
Kamai T, Tsujii T, Arai K, Takagi K, Asami H, Ito Y et al. (2003). Clin Cancer Res 9: 2632–2641.
Kaverina I, Krylyshkina O, Small JV . (2002). Int J Biochem Cell Biol 34: 746–761.
Keely P, Parise L, Juliano R . (1998). Trends Cell Biol 8: 101–106.
Kiefer JA, Farach-Carson MC . (2001). Matrix Biol 20: 429–437.
Kimura G, Kasua J, Giannini S, Honda Y, Mohan S, Kawachi M et al. (1996). Int J Urol 3: 39–46.
Kjoller L, Hall A . (1999). Exp Cell Res 253: 166–179.
Kleer CG, van Golen KL, Zhang Y, Wu ZF, Rubin MA, Merajver SD . (2002). Am J Pathol 160: 579–584.
Kondo T, Sentani K, Oue N, Yoshida K, Nakayama H, Yasui W . (2004). Pathobiology 71: 19–25.
Kwon T, Kwon DY, Chun J, Kim JH, Kang SS . (2000). J Biol Chem 275: 423–428.
Lopez T, Hanahan D . (2002). Cancer Cell 1: 339–353.
Marionnet C, Lalou C, Mollier K, Chazal M, Delestaing G, Compan D et al. (2003). Oncogene 22: 3500–3505.
Meyer GE, Shelden E, Kim B, Feldman EL . (2001). Oncogene 20: 7542–7550.
Mitsiades CS, Mitsiades N . (2005). Expert Rev Anticancer Ther 5: 487–499.
Moorman JP, Luu D, Wickham J, Bobak DA, Hahn CS . (1999). Oncogene 18: 47–57.
Moscow JA, He R, Gnarra JR, Knutsen T, Weng Y, Zhao WP et al. (1994). Oncogene 9: 189–194.
Nobes CD, Hall A . (1995). Cell 81: 53–62.
Olson MF . (1996). J Mol Med 74: 563–571.
Pienta KJ, Sandler H, Sanda MG . In: Pazdur R, Coja LR, Hoskins WJ, Wagman LD (eds). Cancer management: a multidisciplinary approach. 3rd edn. PRR Publishing: Melville, NY, 1999, pp 193–203.
Price LS, Collard JG . (2001). Semin Cancer Biol 11: 167–173.
Ridley AJ, Paterson HF, Johnston CL, Diekmann D, Hall A . (1992). Cell 70: 401–410.
Ridley AJ . (2001). J Cell Sci 114: 2713–2722.
Ridley AJ, Hall A . (1992a). Cell 70: 389–399.
Ridley AJ, Hall A . (1992b). Cold Spring Harb Symp Quant Biol 57: 661–671.
Rubin J, Chung LW, Fan X, Zhu L, Murphy TC, Nanes MS et al. (2004). Prostate 58: 41–49.
Sahai E, Marshall CJ . (2002). Nat Rev Cancer 2: 133–142.
Sander EE, ten Klooster JP, van Delft S, van der Kammen RA, Collard JG . (1999). J Cell Biol 147: 1009–1022.
Shinto E, Tsuda H, Matsubara O, Mochizuki H . (2003). Nippon Rinsho 61 (Suppl 7): 215–219.
Somlyo AV, Phelps C, Dipierro C, Eto M, Read P, Barrett M et al. (2003). FASEB J 17: 223–234.
Somlyo AV, Bradshaw D, Ramos S, Murphy C, Myers CE, Somlyo AP . (2000). Biochem Biophys Res Commun 269: 652–659.
Suwa H, Ohshio G, Imamura T, Watanabe G, Arii S, Imamura M et al. (1998). Br J Cancer 77: 147–152.
Takai Y, Sasaki T, Matozaki T . (2001). Physiol Rev 81: 153–208.
Tanno S, Tanno S, Mitsuuchi Y, Altomare DA, Xiao GH, Testa JR . (2001). Cancer Res 61: 589–593.
Thalmann GN, Sikes RA, Wu TT, Degeorges A, Chang SM, Ozen M et al. (2000). Prostate 44: 91–103.
Turner CE . (2000). J Cell Sci 113 (Part 23): 4139–4140.
van Golen KL, Davies S, Wu ZF, Wang Y, Bucana CD, Root H et al. (1999). Clin Cancer Res 5: 2511–2519.
van Golen KL, Wu ZF, Qiao XT, Bao LW, Merajver SD . (2000a). Cancer Res 60: 5832–5838.
van Golen KL, Wu ZF, Qiao XT, Bao L, Merajver SD . (2000b). Neoplasia 2: 418–425.
van Golen KL, Bao L, DiVito MM, Wu Z, Prendergast GC, Merajver SD . (2002). Mol Cancer Ther 1: 575–583.
van Golen KL . (2003). Breast Cancer Res 5: 174–179.
van Golen KL, Bao LW, Pan Q, Miller FR, Wu ZF, Merajver SD . (2002). Clin Exp Metastasis 19: 301–311.
Wang W, Yang LY, Yang ZL, Huang GW, Lu WQ . (2003). World J Gastroenterol 9: 1950–1953.
West K, Zhang H, Brown M, Nikolopoulos S, Riedy M, Horwitz A et al. (2004). J Cell Biol 154: 161–176.
Yin JJ, Pollock CB, Kelly K . (2005). Cell Res 15: 57–62.
Zaidel-Bar R, Ballestrem C, Kam Z, Geiger B . (2003). J Cell Sci 116: 4605–4613.
Zhang H, Yee D . (2004). Expert Opin Investig Drugs 13: 1569–1577.
Zondag GC, Evers EE, ten Klooster JP, Janssen L, van der Kammen RA, Collard JG . (2000). J Cell Biol 149: 775–782.
Acknowledgements
This work was supported in part by the University of Michigan Comprehensive Cancer Center support grant (5 P30 CA46592) and by a Career Development Award from the Specialized Program of Research Excellence (P50 CA69568, Kenneth Pienta Principal Investigator) at the University of Michigan and the Department of Defense (W81XWH-04-1-0225) (to KLvG). We thank Chris Edwards, MS, for help with the scanning electron micrographs, and Kate Groh, BS, for technical assistance, Drs Kenneth J Pienta, Carlton Cooper and Tim Ritty for insightful discussions, and Robyn Blanzy-Hodges for manuscript preparation.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Yao, H., Dashner, E., van Golen, C. et al. RhoC GTPase is required for PC-3 prostate cancer cell invasion but not motility. Oncogene 25, 2285–2296 (2006). https://doi.org/10.1038/sj.onc.1209260
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1209260
Keywords
This article is cited by
-
RhoC: a fascinating journey from a cytoskeletal organizer to a Cancer stem cell therapeutic target
Journal of Experimental & Clinical Cancer Research (2019)
-
miR-23a promotes invasion of glioblastoma via HOXD10-regulated glial-mesenchymal transition
Signal Transduction and Targeted Therapy (2018)
-
Role of the lncRNA ABHD11-AS1 in the tumorigenesis and progression of epithelial ovarian cancer through targeted regulation of RhoC
Molecular Cancer (2017)
-
A novel microtubule de-stabilizing complementarity-determining region C36L1 peptide displays antitumor activity against melanoma in vitro and in vivo
Scientific Reports (2015)
-
HBx and HBs regulate RhoC expression by upregulating transcription factor Ets-1
Archives of Virology (2013)