Metalloprotease inhibitor profiles of human ADAM8 in vitro and in cell-based assays

Uwe Schlomann 1 , Kristina Dorzweiler 1 , Elisa Nuti 2 , Tiziano Tuccinardi 2 , Armando Rossello 2 , and Jörg W. Bartschhttp://orcid.org/https://orcid.org/0000-0002-2773-3357 1
  • 1 Department of Neurosurgery, University of Marburg, Baldingerstrasse, D-35033 Marburg, Germany
  • 2 Department of Pharmacy, University of Pisa, Via Bonanno 6, I-56126 Pisa, Italy
Uwe Schlomann
  • Department of Neurosurgery, University of Marburg, Baldingerstrasse, D-35033 Marburg, Germany
  • Search for other articles:
  • degruyter.comGoogle Scholar
, Kristina Dorzweiler
  • Department of Neurosurgery, University of Marburg, Baldingerstrasse, D-35033 Marburg, Germany
  • Search for other articles:
  • degruyter.comGoogle Scholar
, Elisa Nuti, Tiziano Tuccinardi, Armando Rossello and Jörg W. BartschORCID iD: https://orcid.org/0000-0002-2773-3357

Abstract

ADAM8 as a membrane-anchored metalloproteinase-disintegrin is upregulated under pathological conditions such as inflammation and cancer. As active sheddase, ADAM8 can cleave several membrane proteins, among them the low-affinity receptor FcεRII CD23. Hydroxamate-based inhibitors are routinely used to define relevant proteinases involved in ectodomain shedding of membrane proteins. However, for ADAM proteinases, common hydroxamates have variable profiles in their inhibition properties, commonly known for ADAM proteinases 9, 10 and 17. Here, we determined the inhibitor profile of human ADAM8 for eight ADAM/MMP inhibitors by in vitro assays using recombinant ADAM8 as well as the in vivo inhibition in cell-based assays using HEK293 cells to monitor the release of soluble CD23 by ADAM8. ADAM8 activity is inhibited by BB94 (Batimastat), GW280264, FC387 and FC143 (two ADAM17 inhibitors), made weaker by GM6001, TAPI2 and BB2516 (Marimastat), while no inhibition was observed for GI254023, an ADAM10 specific inhibitor. Modeling of inhibitor FC143 bound to the catalytic sites of ADAM8 and ADAM17 reveals similar geometries in the pharmacophoric regions of both proteinases, which is different in ADAM10 due to replacement in the S1 position of T300 (ADAM8) and T347 (ADAM17) by V327 (ADAM10). We conclude that ADAM8 inhibitors require maximum selectivity over ADAM17 to achieve specific ADAM8 inhibition.

  • Almahdy, A., Koller, G., Sauro, S., Bartsch, J.W., Sherriff, M., Watson, T.F., and Banerjee, A. (2012). Effects of MMP inhibitors incorporated within dental adhesives. J. Dent. Res. 91, 605–611.

    • Crossref
    • PubMed
    • Export Citation
  • Bartsch, J.W., Wildeboer, D., Koller, G., Naus, S., Rittger, A., Moss, M.L., Minai, Y., and Jockusch, H. (2010). Tumor necrosis factor-α (TNF-α) regulates shedding of TNF-α receptor 1 by the metalloprotease-disintegrin ADAM8: evidence for a protease-regulated feedback loop in neuroprotection. J. Neurosci. 30, 12210–12218.

    • Crossref
    • PubMed
    • Export Citation
  • Berman, H.M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T.N., Weissig, H., Shindyalov, I.N., and Bourne, P.E. (2000). The Protein Data Bank. Nucleic Acids Res. 28, 235–242.

  • Camodeca, C., Nuti, E., Tepshi, L., Boero, S., Tuccinardi, T., Stura, E.A., Poggi, A., Zocchi, M.R., and Rossello, A. (2016). Discovery of a new selective inhibitor of A Disintegrin And Metalloprotease 10 (ADAM-10) able to reduce the shedding of NKG2D ligands in Hodgkin’s lymphoma cell models. Eur. J. Med. Chem. 111, 193–201.

  • Conrad, C., Götte, M., Schlomann, U., Roessler, M., Pagenstecher, A., Anderson, P., Preston, J., Pruessmeyer, J., Ludwig, A., Li, R., et al. (2018). ADAM8 expression in breast cancer derived brain metastases: functional implications on MMP-9 expression and transendothelial migration in breast cancer cells. Int. J. Cancer 142, 779–791.

    • Crossref
    • PubMed
    • Export Citation
  • Dong, F., Eibach, M., Bartsch, J.W., Dolga, A.M., Schlomann, U., Conrad, C., Schieber, S., Schilling, O., Biniossek, M.L., Culmsee, C., et al. (2015). The metalloprotease-disintegrin ADAM8 contributes to temozolomide chemoresistance and enhanced invasiveness of human glioblastoma cells. Neuro. Oncol. 17, 1474–1485.

    • Crossref
    • PubMed
    • Export Citation
  • Fellmann, M., Buschor, P., Röthlisberger, S., Zellweger, F., and Vogel, M. (2015). High affinity targeting of CD23 inhibits IgE synthesis in human B cells. Immun. Inflamm. Dis. 3, 339–349.

    • Crossref
    • Export Citation
  • Fourie, A.M., Coles, F., Moreno, V., and Karlsson, L. (2003). Catalytic activity of ADAM8, ADAM15, and MDC-L (ADAM28) on synthetic peptide substrates and in ectodomain cleavage of CD23. J. Biol. Chem. 278, 30469–30477.

    • Crossref
    • PubMed
    • Export Citation
  • Goddard, T.D., Huang, C.C., Meng, E.C., Pettersen, E.F., Couch, G.S., Morris, J.H., and Ferrin, T.E. (2018). UCSF ChimeraX: Meeting modern challenges in visualization and analysis. Protein. Sci. 27, 14–25.

  • Gómez-Gaviro, M., Domínguez-Luis, M., Canchado, J., Calafat, J., Janssen, H., Lara-Pezzi, E., Fourie, A., Tugores, A., Valenzuela-Fernández, A., Mollinedo, F., et al. (2007). Expression and regulation of the metalloproteinase ADAM-8 during human neutrophil pathophysiological activation and its catalytic activity on L-selectin shedding. J. Immunol. 178, 8053–8063.

  • Ishikawa, N., Daigo, Y., Yasui, W., Inai, K., Nishimura, H., Tsuchiya, E., Kohno, N., and Nakamura, Y. (2004). ADAM8 as a novel serological and histochemical marker for lung cancer. Clin. Cancer Res. 10, 8363–8370.

  • Koller, G., Schlomann, U., Golfi, P., Ferdous, T., Naus, S., and Bartsch, J.W. (2009). ADAM8/MS2/CD156, an emerging drug target in the treatment of inflammatory and invasive pathologies. Curr. Pharm. Des. 15, 2272–2281.

  • Li, C., Cantor, W.J., Nili, N., Robinson, R., Fenkell, L., Tran, Y.L., Whittingham, H.A., Tsui, W., Cheema, A.N., Sparkes, J.D., et al. (2002). Arterial repair after stenting and the effects of GM6001, a matrix metalloproteinase inhibitor. J. Am. Coll. Cardiol. 39, 1852–1858.

    • Crossref
    • PubMed
    • Export Citation
  • Ludwig, A., Hundhausen, C., Lambert, M.H., Broadway, N., Andrews, R.C., Bickett, D.M., Leesnitzer, M.A., and Becherer, J.D. (2005). Metalloproteinase inhibitors for the disintegrin-like metalloproteinases ADAM10 and ADAM17 that differentially block constitutive and phorbol ester-inducible shedding of cell surface molecules. Comb. Chem. High Throughput Screen 8, 161–171.

    • Crossref
    • PubMed
    • Export Citation
  • Maretzky, T., Swendeman, S., Mogollon, E., Weskamp, G., Sahin, U., Reiss, K., and Blobel, C.P. (2017). Characterization of the catalytic properties of the membrane-anchored metalloproteinase ADAM9 in cell-based assays. Biochem. J. 474, 1467–1479.

    • Crossref
    • PubMed
    • Export Citation
  • Miyauchi, M., Koya, J., Arai, S., Yamazaki, S., Honda, A., Kataoka, K., Yoshimi, A., Taoka, K., Kumano, K., and Kurokawa, M. (2018). ADAM8 is an antigen of tyrosine kinase inhibitor-resistant chronic myeloid leukemia cells identified by patient-derived induced pluripotent stem cells. Stem Cell Rep. 10, 1115–1130.

  • Nuti, E., Casalini, F., Avramova, S.I., Santamaria, S., Fabbi, M., Ferrini, S., Marinelli, L., La Pietra, V., Limongelli, V., Novellino, E., et al. (2010). Potent arylsulfonamide inhibitors of tumor necrosis factor-alpha converting enzyme able to reduce activated leukocyte cell adhesion molecule shedding in cancer cell models. J. Med. Chem. 53, 2622–2635.

    • Crossref
    • PubMed
    • Export Citation
  • Nuti, E., Casalini, F., Santamaria, S., Fabbi, M., Carbotti, G., Ferrini, S., Marinelli, L., La Pietra, V., Novellino, E., Camodeca, C., et al. (2013). Selective arylsulfonamide inhibitors of ADAM-17: hit optimization and activity in ovarian cancer cell models. J. Med. Chem. 56, 8089–8103.

    • Crossref
    • PubMed
    • Export Citation
  • Pettersen, E.F., Goddard, T.D., Huang, C.C., Couch, G.S., Greenblatt, D.M., Meng, E.C., and Ferrin, T.E. (2004). UCSF Chimera – a visualization system for exploratory research and analysis. J. Comput. Chem. 25, 1605–1612.

    • Crossref
    • PubMed
    • Export Citation
  • Reiss, K. and Saftig, P. (2009). The “a disintegrin and metalloprotease” (ADAM) family of sheddases: physiological and cellular functions. Semin Cell Dev. Biol. 20, 126–137.

    • Crossref
    • Export Citation
  • Romagnoli, M., Mineva, N.D., Polmear, M., Conrad, C., Srinivasan, S., Loussouarn, D., Barillé-Nion, S., Georgakoudi, I., Dagg, Á., McDermott, E.W., et al. (2014). ADAM8 expression in invasive breast cancer promotes tumor dissemination and metastasis. EMBO Mol. Med. 6, 278–294.

    • Crossref
    • PubMed
    • Export Citation
  • Schlomann, U., Koller, G., Conrad, C., Ferdous, T., Golfi, P., Garcia, A.M., Höfling, S., Parsons, M., Costa, P., Soper, R., et al. (2015). ADAM8 as a drug target in pancreatic cancer. Nat. Commun. 6, 6175.

    • Crossref
    • PubMed
    • Export Citation
  • Schwarz, N., Pruessmeyer, J., Hess, F.M., Dreymueller, D., Pantaler, E., Koelsch, A., Windoffer, R., Voss, M., Sarabi, A., Weber, C., et al. (2010). Requirements for leukocyte transmigration via the transmembrane chemokine CX3CL1. Cell Mol. Life Sci. 67, 4233–4248.

    • Crossref
    • PubMed
    • Export Citation
  • Seals, D.F. and Courtneidge, S.A. (2003). The ADAMs family of metalloproteases: multidomain proteins with multiple functions. Genes Dev. 17, 7–30.

    • Crossref
    • PubMed
    • Export Citation
  • Seegar, T.C.M., Killingsworth, L.B., Saha, N., Meyer, P.A., Patra, D., Zimmerman, B., Janes, P.W., Rubinstein, E., Nikolov, D.B., Skiniotis, G., et al. (2017). Structural basis for regulated proteolysis by the α-secretase ADAM10. Cell 171, 1638–1648.e7.

    • Crossref
    • PubMed
    • Export Citation
  • Ulasov, I., Thaci, B., Sarvaiya, P., Yi, R., Guo, D., Auffinger, B., Pytel, P., Zhang, L., Kim, C.K., Borovjagin, A., et al. (2013). Inhibition of MMP14 potentiates the therapeutic effect of temozolomide and radiation in gliomas. Cancer Med. 2, 457–467.

    • Crossref
    • PubMed
    • Export Citation
  • Valkovskaya, N., Kayed, H., Felix, K., Hartmann, D., Giese, N.A., Osinsky, S.P., Friess, H., and Kleeff, J. (2007). ADAM8 expression is associated with increased invasiveness and reduced patient survival in pancreatic cancer. J. Cell Mol. Med. 11, 1162–1174.

    • Crossref
    • PubMed
    • Export Citation
  • Weskamp, G., Ford, J.W., Sturgill, J., Martin, S., Docherty, A.J., Swendeman, S., Broadway, N., Hartmann, D., Saftig, P., Umland, S., et al. (2006). ADAM10 is a principal ‘sheddase’ of the low-affinity immunoglobulin E receptor CD23. Nat. Immunol. 7, 1293–1298.

    • Crossref
    • PubMed
    • Export Citation
  • Zhang, W., Wan, M., Ma, L., Liu, X., and He, J. (2013). Protective effects of ADAM8 against cisplatin-mediated apoptosis in non-small-cell lung cancer. Cell Biol. Int. 37, 47–53.

    • Crossref
    • PubMed
    • Export Citation
Purchase article
Get instant unlimited access to the article.
$42.00
Log in
Already have access? Please log in.


or
Log in with your institution

Journal + Issues

Search