Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board: Buchner, Johannes / Lei, Ming / Ludwig, Stephan / Thomas, Douglas D. / Turk, Boris / Wittinghofer, Alfred


IMPACT FACTOR 2018: 3.014
5-year IMPACT FACTOR: 3.162

CiteScore 2018: 3.09

SCImago Journal Rank (SJR) 2018: 1.482
Source Normalized Impact per Paper (SNIP) 2018: 0.820

Online
ISSN
1437-4315
See all formats and pricing
More options …
Volume 400, Issue 6

Issues

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

Uwe Schlomann / Kristina Dorzweiler / Elisa Nuti / Tiziano Tuccinardi / Armando Rossello / Jörg W. BartschORCID iD: https://orcid.org/0000-0002-2773-3357
Published Online: 2019-03-04 | DOI: https://doi.org/10.1515/hsz-2018-0396

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.

This article offers supplementary material which is provided at the end of the article.

Keywords: ADAM8; cell-based assay; ectodomain cleavage; hydroxamates; low-affinity IgE receptor FcεRII (CD23); recombinant protein

References

  • 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.Web of ScienceCrossrefPubMedGoogle Scholar

  • 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.Web of ScienceCrossrefPubMedGoogle Scholar

  • 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.Google Scholar

  • 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.Google Scholar

  • 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.CrossrefPubMedWeb of ScienceGoogle Scholar

  • 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.CrossrefPubMedGoogle Scholar

  • 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.Web of ScienceCrossrefGoogle Scholar

  • 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.CrossrefPubMedGoogle Scholar

  • 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.Web of ScienceGoogle Scholar

  • 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.Google Scholar

  • 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.Google Scholar

  • 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.Google Scholar

  • 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.PubMedCrossrefGoogle Scholar

  • 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.CrossrefPubMedGoogle Scholar

  • 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.Web of ScienceCrossrefPubMedGoogle Scholar

  • 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.Google Scholar

  • 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.PubMedWeb of ScienceCrossrefGoogle Scholar

  • 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.CrossrefWeb of SciencePubMedGoogle Scholar

  • 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.PubMedCrossrefGoogle Scholar

  • 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.Web of ScienceCrossrefGoogle Scholar

  • 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.Web of SciencePubMedGoogle Scholar

  • 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.PubMedWeb of ScienceCrossrefGoogle Scholar

  • 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.Web of ScienceCrossrefPubMedGoogle Scholar

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

  • 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.CrossrefWeb of SciencePubMedGoogle Scholar

  • 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.CrossrefPubMedWeb of ScienceGoogle Scholar

  • 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.Web of SciencePubMedCrossrefGoogle Scholar

  • 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.CrossrefPubMedGoogle Scholar

  • 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.Web of ScienceCrossrefPubMedGoogle Scholar

About the article

Received: 2018-10-10

Accepted: 2018-12-19

Published Online: 2019-03-04

Published in Print: 2019-06-26


Funding Source: Deutsche Forschungsgemeinschaft

Award identifier / Grant number: BA1606/3-1

This work was supported by the Deutsche Forschungsgemeinschaft (Funder Id: 10.13039/501100001659, BA1606/3-1 to J.W.B. and U.S.) and by the University of Pisa (PRA_2018_20). We thank Sarah Koch (Marburg) for help with enzyme assays, Luciana Marinelli and Valeria La Pietra (Naples) for providing us with the docking model ADAM17/FC143, Muriel Bartsch for help with IC50 calculations, and Vincent Dive (Gif-sur-Yvette, France) for helpful discussions on the ADAM8 structure.


Citation Information: Biological Chemistry, Volume 400, Issue 6, Pages 801–810, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: https://doi.org/10.1515/hsz-2018-0396.

Export Citation

©2019 Walter de Gruyter GmbH, Berlin/Boston.Get Permission

Supplementary Article Materials

Comments (0)

Please log in or register to comment.
Log in