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Upregulation of PIP3-dependent Rac exchanger 1 (P-Rex1) promotes prostate cancer metastasis

Abstract

Excessive activation of G-protein-coupled receptor (GPCR) and receptor tyrosine kinase (RTK) pathways has been linked to prostate cancer metastasis. Rac activation by guanine nucleotide exchange factors (GEFs) plays an important role in directional cell migration, a critical step of tumor metastasis cascades. We found that the upregulation of P-Rex1, a Rac-selective GEF synergistically activated by Gβγ freed during GPCR signaling, and PIP3, generated during either RTK or GPCR signaling, strongly correlates with metastatic phenotypes in both prostate cancer cell lines and human prostate cancer specimens. Silencing endogenous P-Rex1 in metastatic prostate cancer PC-3 cells selectively inhibited Rac activity and reduced cell migration and invasion in response to ligands of both epidermal growth factor receptor and G-protein-coupled CXC chemokine receptor 4. Conversely, expression of recombinant P-Rex1, but not its ‘GEF-dead’ mutant, in non-metastatic prostate cancer cells, such as CWR22Rv1, increased cell migration and invasion through Rac-dependent lamellipodia formation. More importantly, using a mouse xenograft model, we showed that the expression of P-Rex1, but not its mutant, induced lymph node metastasis of CWR22Rv1 cells without an effect on primary tumor growth. Thus, by functioning as a coincidence detector of chemotactic signals from both GPCRs and RTKs, P-Rex1-dependent activation of Rac promotes prostate cancer metastasis.

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References

  • Albini A, Benelli R . (2007). The chemoinvasion assay: a method to assess tumor and endothelial cell invasion and its modulation. Nat Protoc 2: 504–511.

    Article  CAS  Google Scholar 

  • Arya M, Patel HR, McGurk C, Tatoud R, Klocker H, Masters J et al. (2004). The importance of the CXCL12-CXCR4 chemokine ligand-receptor interaction in prostate cancer metastasis. J Exp Ther Oncol 4: 291–303.

    CAS  PubMed  Google Scholar 

  • Barber MA, Donald S, Thelen S, Anderson KE, Thelen M, Welch HC . (2007). Membrane translocation of P-Rex1 is mediated by G protein betagamma subunits and phosphoinositide 3-kinase. J Biol Chem 282: 29967–29976.

    Article  CAS  Google Scholar 

  • Bex A, Lummen G, Rembrink K, Otto T, Metz K, Rubben H . (1999). Influence of pertussis toxine on local progression and metastasis after orthotopic implantation of the human prostate cancer cell line PC3 in nude mice. Prostate Cancer Prostatic Dis 2: 36–40.

    Article  CAS  Google Scholar 

  • Bonacci TM, Mathews JL, Yuan C, Lehmann DM, Malik S, Wu D et al. (2006). Differential targeting of Gbetagamma-subunit signaling with small molecules. Science 312: 443–446.

    Article  CAS  Google Scholar 

  • Bookout AL, Finney AE, Guo R, Peppel K, Koch WJ, Daaka Y . (2003). Targeting Gbetagamma signaling to inhibit prostate tumor formation and growth. J Biol Chem 278: 37569–37573.

    Article  CAS  Google Scholar 

  • Cantley LC . (2002). The phosphoinositide 3-kinase pathway. Science 296: 1655–1657.

    Article  CAS  Google Scholar 

  • Cao X, Qin J, Xie Y, Khan O, Dowd F, Scofield M et al. (2006). Regulator of G-protein signaling 2 (RGS2) inhibits androgen-independent activation of androgen receptor in prostate cancer cells. Oncogene 25: 3719–3734.

    Article  CAS  Google Scholar 

  • Ching KZ, Ramsey E, Pettigrew N, D′Cunha R, Jason M, Dodd JG . (1993). Expression of mRNA for epidermal growth factor, transforming growth factor-alpha and their receptor in human prostate tissue and cell lines. Mol Cell Biochem 126: 151–158.

    Article  CAS  Google Scholar 

  • Daaka Y . (2004). G proteins in cancer: the prostate cancer paradigm. Sci STKE 2004: re2.

    PubMed  Google Scholar 

  • Dada S, Demartines N, Dormond O . (2008). mTORC2 regulates PGE2-mediated endothelial cell survival and migration. Biochem Biophys Res Commun 372: 875–879.

    Article  CAS  Google Scholar 

  • Dorsam RT, Gutkind JS . (2007). G-protein-coupled receptors and cancer. Nat Rev Cancer 7: 79–94.

    Article  CAS  Google Scholar 

  • Engers R, Mueller M, Walter A, Collard JG, Willers R, Gabbert HE . (2006). Prognostic relevance of Tiam1 protein expression in prostate carcinomas. Br J Cancer 95: 1081–1086.

    Article  CAS  Google Scholar 

  • Fingar DC, Blenis J . (2004). Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression. Oncogene 23: 3151–3171.

    Article  CAS  Google Scholar 

  • Gao X, Mohsin SK, Gatalica Z, Fu G, Sharma P, Nawaz Z . (2005). Decreased expression of e6-associated protein in breast and prostate carcinomas. Endocrinology 146: 1707–1712.

    Article  CAS  Google Scholar 

  • Gao Y, Dickerson JB, Guo F, Zheng J, Zheng Y . (2004). Rational design and characterization of a Rac GTPase-specific small molecule inhibitor. Proc Natl Acad Sci USA 101: 7618–7623.

    Article  CAS  Google Scholar 

  • Hernandez-Negrete I, Carretero-Ortega J, Rosenfeldt H, Hernandez-Garcia R, Calderon-Salinas JV, Reyes-Cruz G et al. (2007). P-Rex1 links mammalian target of rapamycin signaling to Rac activation and cell migration. J Biol Chem 282: 23708–23715.

    Article  CAS  Google Scholar 

  • Hill K, Krugmann S, Andrews SR, Coadwell WJ, Finan P, Welch HC et al. (2005). Regulation of P-Rex1 by phosphatidylinositol (3,4,5)-trisphosphate and Gbetagamma subunits. J Biol Chem 280: 4166–4173.

    Article  CAS  Google Scholar 

  • Hoffman GR, Cerione RA . (2002). Signaling to the Rho GTPases: networking with the DH domain. FEBS Lett 513: 85–91.

    Article  CAS  Google Scholar 

  • Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ . (2007). Cancer statistics, 2007. CA Cancer J Clin 57: 43–66.

    Article  Google Scholar 

  • Jimenez-Sainz MC, Fast B, Mayor Jr F, Aragay AM . (2003). Signaling pathways for monocyte chemoattractant protein 1-mediated extracellular signal-regulated kinase activation. Mol Pharmacol 64: 773–782.

    Article  CAS  Google Scholar 

  • Kedrin D, van RJ, Hernandez L, Condeelis J, Segall JE . (2007). Cell motility and cytoskeletal regulation in invasion and metastasis. J Mammary Gland Biol Neoplasia 12: 143–152.

    Article  Google Scholar 

  • Kelly P, Stemmle LN, Madden JF, Fields TA, Daaka Y, Casey PJ . (2006). A role for the G12 family of heterotrimeric G proteins in prostate cancer invasion. J Biol Chem 281: 26483–26490.

    Article  CAS  Google Scholar 

  • Knight-Krajewski S, Welsh CF, Liu Y, Lyons LS, Faysal JM, Yang ES et al. (2004). Deregulation of the Rho GTPase, Rac1, suppresses cyclin-dependent kinase inhibitor p21(CIP1) levels in androgen-independent human prostate cancer cells. Oncogene 23: 5513–5522.

    Article  CAS  Google Scholar 

  • Kovar JL, Johnson MA, Volcheck WM, Chen J, Simpson MA . (2006). Hyaluronidase expression induces prostate tumor metastasis in an orthotopic mouse model. Am J Pathol 169: 1415–1426.

    Article  CAS  Google Scholar 

  • Lehmann DM, Seneviratne AM, Smrcka AV . (2008). Small molecule disruption of G protein beta gamma subunit signaling inhibits neutrophil chemotaxis and inflammation. Mol Pharmacol 73: 410–418.

    Article  CAS  Google Scholar 

  • Lu Y, Cai Z, Xiao G, Liu Y, Keller ET, Yao Z et al. (2007). CCR2 expression correlates with prostate cancer progression. J Cell Biochem 101: 676–685.

    Article  CAS  Google Scholar 

  • Ma AD, Metjian A, Bagrodia S, Taylor S, Abrams CS . (1998). Cytoskeletal reorganization by G protein-coupled receptors is dependent on phosphoinositide 3-kinase gamma, a Rac guanosine exchange factor, and Rac. Mol Cell Biol 18: 4744–4751.

    Article  CAS  Google Scholar 

  • Mensing H, Pontz BF, Muller PK, Gauss-Muller V . (1983). A study on fibroblast chemotaxis using fibronectin and conditioned medium as chemoattractants. Eur J Cell Biol 29: 268–273.

    CAS  PubMed  Google Scholar 

  • Mimeault M, Batra SK . (2006). Recent advances on multiple tumorigenic cascades involved in prostatic cancer progression and targeting therapies. Carcinogenesis 27: 1–22.

    Article  CAS  Google Scholar 

  • Minard ME, Kim LS, Price JE, Gallick GE . (2004). The role of the guanine nucleotide exchange factor Tiam1 in cellular migration, invasion, adhesion and tumor progression. Breast Cancer Res Treat 84: 21–32.

    Article  CAS  Google Scholar 

  • Moepps B, Frodl R, Rodewald HR, Baggiolini M, Gierschik P . (1997). Two murine homologues of the human chemokine receptor CXCR4 mediating stromal cell-derived factor 1alpha activation of Gi2 are differentially expressed in vivo. Eur J Immunol 27: 2102–2112.

    Article  CAS  Google Scholar 

  • Neptune ER, Iiri T, Bourne HR . (1999). Galphai is not required for chemotaxis mediated by Gi-coupled receptors. J Biol Chem 274: 2824–2828.

    Article  CAS  Google Scholar 

  • Rosenfeldt H, Vazquez-Prado J, Gutkind JS . (2004). P-REX2, a novel PI-3-kinase sensitive Rac exchange factor. FEBS Lett 572: 167–171.

    Article  CAS  Google Scholar 

  • Schiller MR . (2006). Coupling receptor tyrosine kinases to Rho GTPases--GEFs what′s the link. Cell Signal 18: 1834–1843.

    Article  CAS  Google Scholar 

  • Servitja JM, Marinissen MJ, Sodhi A, Bustelo XR, Gutkind JS . (2003). Rac1 function is required for Src-induced transformation. Evidence of a role for Tiam1 and Vav2 in Rac activation by Src. J Biol Chem 278: 34339–34346.

    Article  CAS  Google Scholar 

  • Steeg PS, Theodorescu D . (2008). Metastasis: a therapeutic target for cancer. Nat Clin Pract Oncol 5: 206–219.

    Article  CAS  Google Scholar 

  • Sun D, Xu D, Zhang B . (2006). Rac signaling in tumorigenesis and as target for anticancer drug development. Drug Resist Updat 9: 274–287.

    Article  CAS  Google Scholar 

  • Wang Z, Dong X, Li Z, Smith JD, Wu D . (2008). Lack of a significant role of P-Rex1, a major regulator of macrophage Rac1 activation and chemotaxis, in atherogenesis. Prostaglandins Other Lipid Mediat 87: 9–13.

    Article  CAS  Google Scholar 

  • Welch HC, Coadwell WJ, Ellson CD, Ferguson GJ, Andrews SR, Erdjument-Bromage H et al. (2002). P-Rex1, a PtdIns(3,4,5)P3- and Gbetagamma-regulated guanine-nucleotide exchange factor for Rac. Cell 108: 809–821.

    Article  CAS  Google Scholar 

  • Welch HC, Condliffe AM, Milne LJ, Ferguson GJ, Hill K, Webb LM et al. (2005). P-Rex1 regulates neutrophil function. Curr Biol 15: 1867–1873.

    Article  CAS  Google Scholar 

  • Yamaguchi H, Condeelis J . (2007). Regulation of the actin cytoskeleton in cancer cell migration and invasion. Biochim Biophys Acta 1773: 642–652.

    Article  CAS  Google Scholar 

  • Yamazaki D, Kurisu S, Takenawa T . (2005). Regulation of cancer cell motility through actin reorganization. Cancer Sci 96: 379–386.

    Article  CAS  Google Scholar 

  • Yoshizawa M, Kawauchi T, Sone M, Nishimura YV, Terao M, Chihama K et al. (2005). Involvement of a Rac activator,P-Rex1, in neurotrophin-derived signaling and neuronal migration. J Neurosci 25: 4406–4419.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported in part by Nebraska State Grant LB595, NIH 1R011CA125661 and by the Department of Defense Prostate Cancer Research Program W81XWH-07-1-0189 (YT). We thank Dr Laura Hansen for helpful comments and discussions; Dr Haihong Jiang, Lyudmila Batalkina, Dr Greg Perry and Lisa Linder-Stephenson for their technical assistance. The project described was also supported by Grant G20RR024001 from the National Center for Research Resources. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

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Qin, J., Xie, Y., Wang, B. et al. Upregulation of PIP3-dependent Rac exchanger 1 (P-Rex1) promotes prostate cancer metastasis. Oncogene 28, 1853–1863 (2009). https://doi.org/10.1038/onc.2009.30

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