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Inhibition of ovarian tumor cell invasiveness by targeting SYK in the tyrosine kinase signaling pathway

Oncogene volume 37, pages 3778–3789 (2018)Cite this article

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Abstract

Cell motility and invasiveness are prerequisites for dissemination, and largely account for cancer mortality. We have identified an actionable kinase, spleen tyrosine kinase (SYK), which is keenly tightly associated with tumor progression in ovarian cancer. Here, we report that active recombinant SYK directly phosphorylates cortactin and cofilin, which are critically involved in assembly and dynamics of actin filament through phosphorylation signaling. Enhancing SYK activity by inducing expression of a constitutively active SYK mutant, SYK130E, increased growth factor-stimulated migration and invasion of ovarian cancer cells, which was abrogated by cortactin knockdown. Similarly, SYK inhibitors significantly decreased invasion of ovarian cancer cells across basement membrane in real-time transwell assays and in 3D tumor spheroid models. SYK inactivation by targeted gene knockout or by small molecule inhibition reduced actin polymerization. Collectively, this study reported a new mechanism by which SYK signaling regulates ovarian cancer cell motility and invasiveness, and suggest a target-based strategy to prevent or suppress the advancement of ovarian malignancies.

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References

  1. Bordeleau F, Alcoser TA, Reinhart-King CA. Physical biology in cancer. 5. The rocky road of metastasis: the role of cytoskeletal mechanics in cell migratory response to 3D matrix topography. Am J Physiol Cell Physiol. 2014;306:C110–20.

    Article  CAS  Google Scholar 

  2. Yamaguchi H, Condeelis J. Regulation of the actin cytoskeleton in cancer cell migration and invasion. Biochim Biophys Acta. 2007;1773:642–52.

    Article  CAS  Google Scholar 

  3. Hoon JL, Tan MH, Koh CG. The regulation of cellular responses to mechanical cues by Rho GTPases. Cells. 2016;5:17–37.

    Article  Google Scholar 

  4. Yap KL, Fraley SI, Thiaville MM, Jinawath N, Nakayama K, Wang J, et al. NAC1 is an actin-binding protein that is essential for effective cytokinesis in cancer cells. Cancer Res. 2012;72:4085–96.

    Article  CAS  Google Scholar 

  5. Paz H, Pathak N, Yang J. Invading one step at a time: the role of invadopodia in tumor metastasis. Oncogene. 2014;33:4193–202.

    Article  CAS  Google Scholar 

  6. Hastie EL, Sherwood DR. A new front in cell invasion: the invadopodial membrane. Eur J Cell Biol. 2016;95:441–8.

    Article  CAS  Google Scholar 

  7. Linder S, Wiesner C, Himmel M. Degrading devices: invadosomes in proteolytic cell invasion. Annu Rev Cell Dev Biol. 2011;27:185–211.

    Article  CAS  Google Scholar 

  8. Yu Y, Gaillard S, Phillip JM, Huang TC, Pinto SM, Tessarollo NG, et al. Inhibition of spleen tyrosine kinase potentiates paclitaxel-induced cytotoxicity in ovarian cancer cells by stabilizing microtubules. Cancer Cell. 2015;28:82–96.

    Article  CAS  Google Scholar 

  9. Mocsai A, Ruland J, Tybulewicz VL. The SYK tyrosine kinase: a crucial player in diverse biological functions. Nat Rev Immunol. 2010;10:387–402.

    Article  CAS  Google Scholar 

  10. Kurosaki T, Johnson SA, Pao L, Sada K, Yamamura H, Cambier JC. Role of the Syk autophosphorylation site and SH2 domains in B cell antigen receptor signaling. J Exp Med. 1995;182:1815–23.

    Article  CAS  Google Scholar 

  11. Tsang E, Giannetti AM, Shaw D, Dinh M, Tse JK, Gandhi S, et al. Molecular mechanism of the Syk activation switch. J Biol Chem. 2008;283:32650–9.

    Article  CAS  Google Scholar 

  12. Cheng S, Coffey G, Zhang XH, Shaknovich R, Song Z, Lu P, et al. SYK inhibition and response prediction in diffuse large B-cell lymphoma. Blood. 2011;118:6342–52.

    Article  CAS  Google Scholar 

  13. Young RM, Hardy IR, Clarke RL, Lundy N, Pine P, Turner BC, et al. Mouse models of non-Hodgkin lymphoma reveal Syk as an important therapeutic target. Blood. 2009;113:2508–16.

    Article  CAS  Google Scholar 

  14. Luangdilok S, Box C, Patterson L, Court W, Harrington K, Pitkin L, et al. Syk tyrosine kinase is linked to cell motility and progression in squamous cell carcinomas of the head and neck. Cancer Res. 2007;67:7907–16.

    Article  CAS  Google Scholar 

  15. Lu J, Lin WH, Chen SY, Longnecker R, Tsai SC, Chen CL, et al. Syk tyrosine kinase mediates Epstein-Barr virus latent membrane protein 2A-induced cell migration in epithelial cells. J Biol Chem. 2006;281:8806–14.

    Article  CAS  Google Scholar 

  16. Prinos P, Garneau D, Lucier JF, Gendron D, Couture S, Boivin M, et al. Alternative splicing of SYK regulates mitosis and cell survival. Nat Struct Mol Biol. 2011;18:673–9.

    Article  CAS  Google Scholar 

  17. Layton T, Stalens C, Gunderson F, Goodison S, Silletti S. Syk tyrosine kinase acts as a pancreatic adenocarcinoma tumor suppressor by regulating cellular growth and invasion. Am J Pathol. 2009;175:2625–36.

    Article  CAS  Google Scholar 

  18. Sharman J, Hawkins M, Kolibaba K, Boxer M, Klein L, Wu M, et al. An open-label phase 2 trial of entospletinib (GS-9973), a selective spleen tyrosine kinase inhibitor, in chronic lymphocytic leukemia. Blood. 2015;125:2336–43.

    Article  CAS  Google Scholar 

  19. Weinblatt ME, Kavanaugh A, Genovese MC, Musser TK, Grossbard EB, Magilavy DB. An oral spleen tyrosine kinase (Syk) inhibitor for rheumatoid arthritis. N Engl J Med. 2010;363:1303–12.

    Article  CAS  Google Scholar 

  20. Weinblatt ME, Kavanaugh A, Burgos-Vargas R, Dikranian AH, Medrano-Ramirez G, Morales-Torres JL, et al. Treatment of rheumatoid arthritis with a Syk kinase inhibitor: a twelve-week, randomized, placebo-controlled trial. Arthritis Rheum. 2008;58:3309–18.

    Article  CAS  Google Scholar 

  21. Friedberg JW, Sharman J, Sweetenham J, Johnston PB, Vose JM, Lacasce A, et al. Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood. 2010;115:2578–85.

    Article  CAS  Google Scholar 

  22. Lua BL, Low BC. Cortactin phosphorylation as a switch for actin cytoskeletal network and cell dynamics control. FEBS Lett. 2005;579:577–85.

    Article  CAS  Google Scholar 

  23. Arber S, Barbayannis FA, Hanser H, Schneider C, Stanyon CA, Bernard O, et al. Regulation of actin dynamics through phosphorylation of cofilin by LIM-kinase. Nature. 1998;393:805–9.

    Article  CAS  Google Scholar 

  24. Huang C, Liu J, Haudenschild CC, Zhan X. The role of tyrosine phosphorylation of cortactin in the locomotion of endothelial cells. J Biol Chem. 1998;273:25770–6.

    Article  CAS  Google Scholar 

  25. Yoo Y, Ho HJ, Wang C, Guan JL. Tyrosine phosphorylation of cofilin at Y68 by v-Src leads to its degradation through ubiquitin-proteasome pathway. Oncogene. 2010;29:263–72.

    Article  CAS  Google Scholar 

  26. Wu PH, Phillip JM, Khatau SB, Chen WC, Stirman J, Rosseel S, et al. Evolution of cellular morpho-phenotypes in cancer metastasis. Sci Rep. 2015;5:18437.

    Article  CAS  Google Scholar 

  27. Inagaki N, Katsuno H. Actin waves: origin of cell polarization and migration? Trends Cell Biol. 2017;27:515–26.

    Article  CAS  Google Scholar 

  28. Riedl J, Crevenna AH, Kessenbrock K, Yu JH, Neukirchen D, Bista M, et al. Lifeact: a versatile marker to visualize F-actin. Nat Methods. 2008;5:605–7.

    Article  CAS  Google Scholar 

  29. Gagliardi PA, Puliafito A, di Blasio L, Chianale F, Somale D, Seano G, et al. Real-time monitoring of cell protrusion dynamics by impedance responses. Sci Rep. 2015;5:10206.

    Article  Google Scholar 

  30. Xue L, Wang WH, Iliuk A, Hu L, Galan JA, Yu S, et al. Sensitive kinase assay linked with phosphoproteomics for identifying direct kinase substrates. Proc Natl Acad Sci USA. 2012;109:5615–20.

    Article  CAS  Google Scholar 

  31. Pearce G, Audzevich T, Jessberger R. SYK regulates B-cell migration by phosphorylation of the F-actin interacting protein SWAP-70. Blood. 2011;117:1574–84.

    Article  CAS  Google Scholar 

  32. Ocana-Morgner C, Wahren C, Jessberger R. SWAP-70 regulates RhoA/RhoB-dependent MHCII surface localization in dendritic cells. Blood. 2009;113:1474–82.

    Article  CAS  Google Scholar 

  33. Beitz LO, Fruman DA, Kurosaki T, Cantley LC, Scharenberg AM. SYK is upstream of phosphoinositide 3-kinase in B cell receptor signaling. J Biol Chem. 1999;274:32662–6.

    Article  CAS  Google Scholar 

  34. Stephens LR, Anderson KE, Hawkins PT. Src family kinases mediate receptor-stimulated, phosphoinositide 3-kinase-dependent, tyrosine phosphorylation of dual adaptor for phosphotyrosine and 3-phosphoinositides-1 in endothelial and B cell lines. J Biol Chem. 2001;276:42767–73.

    Article  CAS  Google Scholar 

  35. Hatton O, Lambert SL, Krams SM, Martinez OM. Src kinase and Syk activation initiate PI3K signaling by a chimeric latent membrane protein 1 in Epstein-Barr virus (EBV)+B cell lymphomas. PLoS ONE. 2012;7:e42610.

    Article  CAS  Google Scholar 

  36. Moon KD, Post CB, Durden DL, Zhou Q, De P, Harrison ML, et al. Molecular basis for a direct interaction between the Syk protein-tyrosine kinase and phosphoinositide 3-kinase. J Biol Chem. 2005;280:1543–51.

    Article  CAS  Google Scholar 

  37. Yu L, Wang Y, Yao Y, Li W, Lai Q, Li J, et al. Eradication of growth of HER2-positive ovarian cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate in mouse xenograft model. International journal of gynecological cancer: official journal of the International Gynecological Cancer. Int J Gynecol Cancer. 2014;24:1158–64.

    Article  Google Scholar 

  38. Macdonald-Obermann JL, Pike LJ. Different epidermal growth factor (EGF) receptor ligands show distinct kinetics and biased or partial agonism for homodimer and heterodimer formation. J Biol Chem. 2014;289:26178–88.

    Article  CAS  Google Scholar 

  39. Li Y, Macdonald-Obermann J, Westfall C, Piwnica-Worms D, Pike LJ. Quantitation of the effect of ErbB2 on epidermal growth factor receptor binding and dimerization. J Biol Chem. 2012;287:31116–25.

    Article  CAS  Google Scholar 

  40. Cox D, Chang P, Kurosaki T, Greenberg S. Syk tyrosine kinase is required for immunoreceptor tyrosine activation motif-dependent actin assembly. J Biol Chem. 1996;271:16597–602.

    Article  CAS  Google Scholar 

  41. Jaumouille V, Farkash Y, Jaqaman K, Das R, Lowell CA, Grinstein S. Actin cytoskeleton reorganization by Syk regulates Fcgamma receptor responsiveness by increasing its lateral mobility and clustering. Dev Cell. 2014;29:534–46.

    Article  CAS  Google Scholar 

  42. Coopman PJ, Do MT, Barth M, Bowden ET, Hayes AJ, Basyuk E, et al. The Syk tyrosine kinase suppresses malignant growth of human breast cancer cells. Nature. 2000;406:742–7.

    Article  CAS  Google Scholar 

  43. Ghotra VP, He S, van der Horst G, Nijhoff S, de Bont H, Lekkerkerker A, et al. SYK is a candidate kinase target for the treatment of advanced prostate cancer. Cancer Res. 2015;75:230–40.

    Article  CAS  Google Scholar 

  44. Zhang X, Shrikhande U, Alicie BM, Zhou Q, Geahlen RL. Role of the protein tyrosine kinase Syk in regulating cell-cell adhesion and motility in breast cancer cells. Mol Cancer Res: 2009;7:634–44.

    Article  CAS  Google Scholar 

  45. Ruschel A, Ullrich A. Protein tyrosine kinase Syk modulates EGFR signalling in human mammary epithelial cells. Cell Signal. 2004;16:1249–61.

    Article  CAS  Google Scholar 

  46. Kurman RJ, Shih IeM. The dualistic model of ovarian carcinogenesis: revisited, revised, and expanded. Am J Pathol. 2016;186:733–47.

    Article  Google Scholar 

  47. Kunwar S, Devkota AR, Ghimire DK. Fostamatinib, an oral spleen tyrosine kinase inhibitor, in the treatment of rheumatoid arthritis: a meta-analysis of randomized controlled trials. Rheumatol Int. 2016;36:1077–87.

    Article  CAS  Google Scholar 

  48. Pohl G, Ho CL, Kurman RJ, Bristow R, Wang TL, Shih Ie M. Inactivation of the mitogen-activated protein kinase pathway as a potential target-based therapy in ovarian serous tumors with KRAS or BRAF mutations. Cancer Res. 2005;65:1994–2000.

    Article  CAS  Google Scholar 

  49. Ran FA, Hsu PD, Wright J, Agarwala V, Scott DA, Zhang F. Genome engineering using the CRISPR-Cas9 system. Nat Protoc. 2013;8:2281–308.

    Article  CAS  Google Scholar 

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Acknowledgements

This study was supported by NIH/NCI grants, RO1CA215483 (I.M.S.), UO1CA200469 (I.M.S.), RO1CA148826 (T.L.W.), R21CA187512 (T.L.W.), K22CA212060 (C.H.H.), KO1-CA166576 (M.I.V.), Richard W. TeLinde Research Program (www.gynecologycancer.org), Ovarian Cancer Research Foundation Alliance (OCRFA) Grant # 458972 (I.M.S.), The Honorable Tina Brozman Foundation (I.M.S. and T.L.W.), TEAL award (T.L.W.), and US Department of Defense Ovarian Cancer Consortium grant W81XWH-11-2-0230 (I.M.S. and T.L.W.).

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Authors and Affiliations

  1. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD, 21205, USA

    Yu Yu, Yohan Suryo Rahmanto, Stephanie Gaillard, Ie-Ming Shih & Tian-Li Wang

  2. Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, 21287, USA

    Yu Yu, Yohan Suryo Rahmanto, Chuan-Hsiang Huang, Ie-Ming Shih & Tian-Li Wang

  3. Department of Chemical and Biomolecular Engineering, Physical Sciences-Oncology Center, and Institute for NanoBioTechology, Johns Hopkins University, Baltimore, MD, 21218, USA

    Meng-Horng Lee, Pei-Hsun Wu, Jude M. Phillip & Denis Wirtz

  4. Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA

    Michele I. Vitolo & Stuart S. Martin

  5. Marlene and Stewart Greenebaum National Cancer Institute Cancer Center, University of Maryland School of Medicine, Baltimore, MD, 21201, USA

    Michele I. Vitolo & Stuart S. Martin

  6. Department of Gynecology and Obstetrics, Johns Hopkins Medical Institutions, Baltimore, MD, 21287, USA

    Stephanie Gaillard, Ie-Ming Shih & Tian-Li Wang

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Yu, Y., Suryo Rahmanto, Y., Lee, MH. et al. Inhibition of ovarian tumor cell invasiveness by targeting SYK in the tyrosine kinase signaling pathway. Oncogene 37, 3778–3789 (2018). https://doi.org/10.1038/s41388-018-0241-0

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