title: RhoC promotes metastasis via activation of the Pyk2 pathway in prostate cancer.
abstract: RhoC is a member of the Ras-homologous family of genes which have been implicated in tumorigenesis and tumor progression. However, the exact role of RhoC is controversial and is yet to be clarified. We have examined the effect of RhoC on prostate tumor cells and found that RhoC had no effect on cell proliferation in vitro or on tumor growth in mice. However, RhoC significantly enhanced the metastatic ability of the tumor cells in these animals, suggesting that RhoC affects only the metastasis but not the growth of prostate tumor cells. The results of our immunohistochemical analyses on tumor specimens from 63 patients with prostate cancer indicate that RhoC expression had no significant correlation with Gleason grade. However, the expression of RhoC showed significant positive correlation with both lymph node and distant metastasis, and it was inversely correlated with patient survival. We also found that RhoC significantly augmented the invasion and motility of prostate tumor cells by activating matrix metalloproteinases 2 and 9 (MMP2 and MMP9) in vitro. The results of our antibody array analysis for signal molecules revealed that RhoC significantly activated kinases including mitogen-activated protein kinase (MAPK), focal adhesion kinase (FAK), Akt, and Pyk2. Inhibition of Pyk2 kinase blocked the RhoC-dependent activation of FAK, MAPK, and Akt, followed by the suppression of MMP2 and MMP9. Inhibitors of both MAPK and Akt also significantly blocked the activities of these MMPs. Therefore, our results indicate that RhoC promotes tumor metastasis in prostate cancer by sequential activation of Pyk2, FAK, MAPK, and Akt followed by the up-regulation of MMP2 and MMP9, which results in the stimulation of invasiveness of tumor cells.
authors.affiliation: Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois 62702, USA.
authors.forename: Megumi
authors.initials: M
authors.lastname: Iiizumi
authors.forename: Sucharita
authors.initials: S
authors.lastname: Bandyopadhyay
authors.forename: Sudha K
authors.initials: SK
authors.lastname: Pai
authors.forename: Misako
authors.initials: M
authors.lastname: Watabe
authors.forename: Shigeru
authors.initials: S
authors.lastname: Hirota
authors.forename: Sadahiro
authors.initials: S
authors.lastname: Hosobe
authors.forename: Taisei
authors.initials: T
authors.lastname: Tsukada
authors.forename: Kunio
authors.initials: K
authors.lastname: Miura
authors.forename: Ken
authors.initials: K
authors.lastname: Saito
authors.forename: Eiji
authors.initials: E
authors.lastname: Furuta
authors.forename: Wen
authors.initials: W
authors.lastname: Liu
authors.forename: Fei
authors.initials: F
authors.lastname: Xing
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Okuda
authors.forename: Aya
authors.initials: A
authors.lastname: Kobayashi
authors.forename: Kounosuke
authors.initials: K
authors.lastname: Watabe
mesh_terms: D000818:Animals; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D004789:Enzyme Activation; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism*; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D015398:Signal Transduction; D015854:Up-Regulation; D020741:rho GTP-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism*; D000075024:rhoC GTP-Binding Protein
chemical_list: D051417:Focal Adhesion Kinase 1; D051418:Focal Adhesion Kinase 2; C496050:PTK2 protein, human; D020928:Mitogen-Activated Protein Kinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; C066690:RHOC protein, human; D020741:rho GTP-Binding Proteins; D000075024:rhoC GTP-Binding Protein
references.citation: Clin Cancer Res. 2003 Nov 1;9(14):5282-6
references.pmid: 14614010
references.citation: Neoplasia. 2005 May;7(5):435-45
references.pmid: 15967096
references.citation: Head Neck. 1998 Dec;20(8):745-52
references.pmid: 9790298
references.citation: Oncogene. 2000 Mar 2;19(10):1318-28
references.pmid: 10713673
references.citation: Nat Rev Cancer. 2002 Feb;2(2):133-42
references.pmid: 12635176
references.citation: Mol Cell Biol. 2005 Aug;25(16):6889-98
references.pmid: 16055703
references.citation: Clin Cancer Res. 2000 Jun;6(6):2417-23
references.pmid: 10873094
references.citation: Nat Rev Cancer. 2001 Nov;1(2):162-8
references.pmid: 11905808
references.citation: Mol Ther. 2005 Feb;11(2):267-74
references.pmid: 15668138
references.citation: Cancer Res. 2007 Nov 15;67(22):10976-83
references.pmid: 18006843
references.citation: Prostate. 1986;9(3):261-81
references.pmid: 3774632
references.citation: Eur J Cancer. 2006 Jul;42(10):1455-65
references.pmid: 16750623
references.citation: Ann Surg Oncol. 1996 Jan;3(1):100-5
references.pmid: 8770310
references.citation: Clin Exp Metastasis. 2002;19(4):301-11
references.pmid: 12090470
references.citation: Oncogene. 1997 Jul 17;15(3):265-74
references.pmid: 9233761
references.citation: Cancer Metastasis Rev. 2006 Mar;25(1):9-34
references.pmid: 16680569
references.citation: Br J Cancer. 2004 Jun 14;90(12):2349-55
references.pmid: 15150600
references.citation: Clin Cancer Res. 2004 Feb 1;10(3):1192-200
references.pmid: 14871999
references.citation: J Invest Dermatol. 2006 Apr;126(4):862-8
references.pmid: 16470169
references.citation: Nat Cell Biol. 2000 May;2(5):249-56
references.pmid: 10806474
references.citation: Int J Cancer. 1996 Oct 9;68(2):164-71
references.pmid: 8900422
references.citation: Prog Biophys Mol Biol. 1999;71(3-4):435-78
references.pmid: 10354709
references.citation: Cancer Res. 2005 Jun 1;65(11):4698-706
references.pmid: 15930288
references.citation: Cancer Res. 2005 Nov 1;65(21):9762-70
references.pmid: 16266997
references.citation: J Cell Physiol. 2006 Jun;207(3):816-28
references.pmid: 16508947
references.citation: Cancer Res. 1999 Apr 15;59(8):2004-10
references.pmid: 10213513
references.citation: Cancer Res. 2004 Nov 1;64(21):7655-60
references.pmid: 15520163
references.citation: Mol Cell Biol. 2004 Apr;24(8):3526-35
references.pmid: 15060171
references.citation: Oncogene. 2006 Apr 13;25(16):2285-96
references.pmid: 16314838
references.citation: Cell. 2004 Jan 23;116(2):167-79
references.pmid: 14744429
references.citation: Clin Cancer Res. 2004 Apr 15;10(8):2742-50
references.pmid: 15102679
references.citation: Oncogene. 2004 Jan 8;23(1):157-67
references.pmid: 14712221
references.citation: Oncogene. 2001 May 10;20(21):2626-35
references.pmid: 11420674
references.citation: Cancer Res. 2007 Nov 1;67(21):10436-44
references.pmid: 17974987
references.citation: Exp Cell Res. 2004 Nov 15;301(1):43-9
references.pmid: 15501444
references.citation: Cancer Res. 2006 Mar 15;66(6):3153-61
references.pmid: 16540666
references.citation: Clin Cancer Res. 2003 Jan;9(1):215-22
references.pmid: 12538472
references.citation: Clin Cancer Res. 2004 Oct 1;10(19):6572-8
references.pmid: 15475446
references.citation: Eur J Biochem. 1999 Aug;263(3):605-11
references.pmid: 10469123
references.citation: Anticancer Res. 2004 Mar-Apr;24(2B):921-7
references.pmid: 15161045
references.citation: Nat Rev Cancer. 2005 Jul;5(7):505-15
references.pmid: 16069815
references.citation: Cancer Res. 2003 Apr 15;63(8):1731-6
references.pmid: 12702552
references.citation: Head Neck. 1998 Oct;20(7):634-9
references.pmid: 9744465
references.citation: J Biol Chem. 1998 Feb 27;273(9):5146-54
references.pmid: 9478968
references.citation: Endocrinology. 2004 Jul;145(7):3324-30
references.pmid: 15070849
references.citation: Cancer. 1999 Oct 15;86(8):1551-6
references.pmid: 10526262
references.citation: Breast Cancer Res Treat. 2005 Sep;93(2):101-10
references.pmid: 16187229
references.citation: Genes Dev. 2005 Sep 1;19(17):1974-9
references.pmid: 16107613
references.citation: J Biol Chem. 1999 Mar 26;274(13):8917-24
references.pmid: 10085136
references.citation: Clin Exp Metastasis. 2000;18(5):423-8
references.pmid: 11467775