Chemotherapy-induced activation of ADAM-17: a novel mechanism of drug resistance in colorectal cancer
Open accessPublished version of a preprint
Abstract
Purpose: We have shown previously that exposure to anticancer drugs can trigger the activation of human epidermal receptor survival pathways in colorectal cancer (CRC). In this study, we examined the role of ADAMs (a disintegrin and metalloproteinases) and soluble growth factors in this acute drug resistance mechanism. Experimental Design: In vitro and in vivo models of CRC were assessed. ADAM-17 activity was measured using a fluorometric assay. Ligand shedding was assessed by ELISA or Western blotting. Apoptosis was assessed by flow cytometry and Western blotting. Results: Chemotherapy (5-fluorouracil) treatment resulted in acute increases in transforming growth factor-α, amphiregulin, and heregulin ligand shedding in vitro and in vivo that correlated with significantly increased ADAM-17 activity. Small interfering RNA–mediated silencing and pharmacologic inhibition confirmed that ADAM-17 was the principal ADAM involved in this prosurvival response. Furthermore, overexpression of ADAM-17 significantly decreased the effect of chemotherapy on tumor growth and apoptosis. Mechanistically, we found that ADAM-17 not only regulated phosphorylation of human epidermal receptors but also increased the activity of a number of other growth factor receptors, such as insulin-like growth factor-I receptor and vascular endothelial growth factor receptor. Conclusions: Chemotherapy acutely activates ADAM-17, which results in growth factor shedding, growth factor receptor activation, and drug resistance in CRC tumors. Thus, pharmacologic inhibition of ADAM-17 in conjunction with chemotherapy may have therapeutic potential for the treatment of CRC. Clin Cancer Res; 16(13); 3378–89. ©2010 AACR.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Bevacizumab plus Irinotecan, Fluorouracil, and Leucovorin for Metastatic Colorectal Cancer
Hurwitz, H., Fehrenbacher, L., Novotny, W., Cartwright, T., Hainsworth, J., Heim, W., Berlin, J., Baron, A., Griffing, S., Holmgren, E., et al. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa032691 · Cited by 10,968 · see citing works
Chou, T.-C., & Talalay, P. (1984) · Advances in Enzyme Regulation · doi:10.1016/0065-2571(84)90007-4 · Cited by 7,178 · see citing works
Untangling the ErbB signalling network
Yarden, Y., & Sliwkowski, M. X. (2001) · Nature Reviews Molecular Cell Biology · doi:10.1038/35052073 · Cited by 6,974 · see citing works
Cetuximab and Chemotherapy as Initial Treatment for Metastatic Colorectal Cancer
Van Cutsem, E., Köhne, C.-H., Hitre, E., Zaluski, J., Chang Chien, C.-R., Makhson, A., D'Haens, G., Pintér, T., Lim, R., Bodoky, G., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0805019 · Cited by 3,877 · see citing works
Epidermal growth factor-related peptides and their receptors in human malignancies.
Salomon, D., Brandt, R., Ciardiello, F., & Normanno, N. (1995) · Critical reviews in oncology/hematology · doi:10.1016/1040-8428(94)00144-i · Cited by 2,860 · see citing works
The ErbB signaling network: receptor heterodimerization in development and cancer
Olayioye, M. A., Neve, R. M., Lane, H. A., & Hynes, N. E. (2000) · The EMBO Journal · doi:10.1093/emboj/19.13.3159 · Cited by 2,438 · see citing works
An Essential Role for Ectodomain Shedding in Mammalian Development
Peschon, J. J., Slack, J. L., Reddy, P., Stocking, K. L., Sunnarborg, S. W., Lee, D. C., Russell, W. E., Castner, B. J., Johnson, R. S., Fitzner, J. N., et al. (1998) · Science · doi:10.1126/science.282.5392.1281 · Cited by 1,606 · see citing works
ADAMs: key components in EGFR signalling and development
Blobel, C. (2005) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1548 · Cited by 1,091 · see citing works
The ADAMs family of metalloproteases: multidomain proteins with multiple functionsPreprint
Seals, D. F., & Courtneidge, S. A. (2003) · Genes & Development · doi:10.1101/gad.1039703 · Cited by 1,058 · see citing works
Ligand-Induced, Receptor-Mediated Dimerization and Activation of EGF Receptor
Schlessinger, J. (2002) · Cell · doi:10.1016/s0092-8674(02)00966-2 · Cited by 995 · see citing works
Distinct roles for ADAM10 and ADAM17 in ectodomain shedding of six EGFR ligands
Şahin, U., Weskamp, G., Kelly, K., Zhou, H., Higashiyama, S., Peschon, J. J., Hartmann, D., Säftig, P., & Blobel, C. (2004) · The Journal of Cell Biology · doi:10.1083/jcb.200307137 · Cited by 979 · see citing works
An Open-and-Shut Case? Recent Insights into the Activation of EGF/ErbB Receptors
Burgess, A. W., Cho, H., Eigenbrot, C. W., Ferguson, K. M., Garrett, T., Leahy, D. J., Lemmon, M. A., Sliwkowski, M. X., Ward, C. W., & Yokoyama, S. (2003) · Molecular Cell · doi:10.1016/s1097-2765(03)00350-2 · Cited by 908 · see citing works
Hundhausen, C., Misztela, D., Berkhout, T. A., BROADWAY, N. M., Säftig, P., Reiß, K., Hartmann, D., Fahrenholz, F., Postina, R., Matthews, V. B., et al. (2003) · Blood · doi:10.1182/blood-2002-12-3775 · Cited by 714 · see citing works
Sunnarborg, S. W., Hinkle, C. L., Stevenson, M. C., Russell, W. E., Raska, C. S., Peschon, J. J., Castner, B. J., GERHART, M. J., Paxton, R. J., Black, R. A., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m112050200 · Cited by 413 · see citing works
Zhou, B.-B., Peyton, M., He, B., Liu, C., Girard, L., Caudler, E., Lo, Y. Y. C., Baribaud, F., Mikami, I., Reguart, N., et al. (2006) · Cancer Cell · doi:10.1016/j.ccr.2006.05.024 · Cited by 370 · see citing works
Jacobs, B., De Roock, W., Piessevaux, H., Van Oirbeek, R., Biesmans, B., De Schutter, J., Fieuws, S., Vandesompele, J., Peeters, M., Van Laethem, J.-L., et al. (2009) · Journal of Clinical Oncology · doi:10.1200/jco.2008.21.3744 · Cited by 368 · see citing works
Non-Oncogene Addiction and the Stress Phenotype of Cancer Cells
Solimini, N. L., Luo, J., & Elledge, S. J. (2007) · Cell · doi:10.1016/j.cell.2007.09.007 · Cited by 366 · see citing works
Dı́az-Rodrı́guez, E., Montero, J. C., Esparı́s-Ogando, A., Yuste, L., & Pandiella, A. (2002) · Molecular Biology of the Cell · doi:10.1091/mbc.01-11-0561 · Cited by 308 · see citing works
Protease-activated Receptor 2 in Colon Cancer
Darmoul, D., Gratio, V., Devaud, H., & Laburthe, M. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m401430200 · Cited by 208 · see citing works
Horiuchi, K., Zhou, H., Kelly, K., Manova, K., & Blobel, C. (2005) · Developmental Biology · doi:10.1016/j.ydbio.2005.05.004 · Cited by 163 · see citing works
Montero, J. C., Yuste, L., Dı́az-Rodrı́guez, E., Esparı́s-Ogando, A., & Pandiella, A. (2000) · Molecular and Cellular Neuroscience · doi:10.1006/mcne.2000.0896 · Cited by 162 · see citing works
ITOH, Y., JOH, T., Tanida, S., et al. (2005) · Cytokine · doi:10.1016/j.cyto.2004.11.005 · Cited by 155 · see citing works
Fischer, O. M., Hart, S., Gschwind, A., Prenzel, N., & Ullrich, A. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.12.5172-5183.2004 · Cited by 151 · see citing works
Cisplatin-induced activation of the EGF receptor
Benhar, M., Engelberg, D., & Levitzki, A. (2002) · Oncogene · doi:10.1038/sj.onc.1205980 · Cited by 146 · see citing works
Fridman, J. S., Caulder, E., Hansbury, M., Liu, X., Yang, G., Wang, Q., Lo, Y. Y. C., Zhou, B. S., Pan, M., Thomas, S. M., et al. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-06-2116 · Cited by 145 · see citing works
Merlos‐Suárez, A., Ruíz-Paz, S., Baselga, J. M., & Arribas, J. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m103488200 · Cited by 132 · see citing works
Merchant, N. B., Voskresensky, I. V., Rogers, C. M., LaFleur, B., Dempsey, P. J., Graves‐Deal, R., Revetta, F. L., Foutch, A. C., Rothenberg, M. L., Washington, M. K., et al. (2008) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-1216 · Cited by 107 · see citing works
Schaeybroeck, S. V., Karaı̈skou, A., Kelly, D. M., Longley, D. B., Galligan, L., Cutsem, E. V., & Johnston, P. (2005) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-05-0328 · Cited by 103 · see citing works
Self-citationThe mechanism of cleavage of EGFR ligands induced by inflammatory cytokines in gastric cancer cells
Tanida, S., Joh, T., Itoh, K., et al. (2004) · Gastroenterology · doi:10.1053/j.gastro.2004.05.017 · Cited by 98 · see citing works
Kaulfuß, S., Burfeind, P., Gaedcke, J., & Scharf, J. (2009) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-09-0058 · Cited by 71 · see citing works
Hagan, M. P., Yacoub, A., & Dent, P. (2004) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-04-0420 · Cited by 54 · see citing works
Targeting the EGFR, VEGFR, and PDGFR on colon cancer cells and stromal cells is required for therapy
Kuwai, T., Nakamura, T., Sasaki, T., et al. (2008) · Clinical & Experimental Metastasis · doi:10.1007/s10585-008-9153-7 · Cited by 39 · see citing works
Schaeybroeck, S. V., Kelly, D. M., Kyula, J., Stokesberry, S. A., Fennell, D. A., Johnston, P. G., & Longley, D. B. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-6736 · Cited by 36 · see citing works
Self-citationPrenen, H., Jacobs, B., Roock, W. D., Oirbeek, R. V., Biesmans, B., Schutter, J. D., Fieuws, S., Laurent‐Puig, P., Cutsem, E. V., & Tejpar, S. (2009) · Journal of Clinical Oncology · doi:10.1200/jco.2009.27.15_suppl.4019 · Cited by 10 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Cancer drug resistance: an evolving paradigm
Holohan, C., Van Schaeybroeck, S., Longley, D. B., & Johnston, P. G. (2013) · Nature Reviews Cancer · doi:10.1038/nrc3599 · Cited by 4,681 · see citing works
Self-citationOncogenic <i>Kras</i> Promotes Chemotherapy-Induced Growth Factor Shedding via ADAM17
Van Schaeybroeck, S., Kyula, J. N., Fenton, A., Fenning, C. S., Sasazuki, T., Shirasawa, S., Longley, D. B., & Johnston, P. G. (2011) · Cancer Research · doi:10.1158/0008-5472.can-10-0714 · Cited by 51 · see citing works
Self-citationDosch, J., Ziemke, E., Wan, S., Luker, K., Welling, T., Hardiman, K., Fearon, E., Thomas, S., Flynn, M., Rios-Doria, J., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.17780 · Cited by 40 · see citing works
Khawaja, H., Briggs, R., Latimer, C. H., Rassel, M., Griffin, D., Hanson, L., Bardelli, A., Di Nicolantonio, F., McDade, S. S., Scott, C. J., et al. (2023) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-22-0301 · Cited by 12 · see citing works
“Acquired AZ’1569-R clones overproduce a wide array of proinflammatory factors We have previously shown that oncogenic KRAS regulates growth factor and/or cytokine shedding andADAM17 activity (30), a protease involved in acute resistance to chemotherapy and targeted therapies (31).”
BackgroundSelf-citation
- Authors
- Kyula, J. N., Van Schaeybroeck, S., Doherty, J., Fenning, C. S., Longley, D. B., & Johnston, P. G.
- Affiliations
- Queen's University Belfast (GB)
- Authors' Affiliation: Drug Resistance Group, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland
- Corresponding author
- Johnston, Patrick G.
- Venue
- Clinical Cancer Research
- Published
- 2010-06-30
- Volume
- 16
- Issue
- 13
- Pages
- 3378-3389
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC2896550
- OpenAlex
- W2021920896
- Cited by
- 99
- References
- 34
- Citations by year
- 2026: 3 · 2024: 6 · 2023: 5 · 2022: 2 · 2021: 8 · 2020: 10 · 2019: 2 · 2018: 9 · 2017: 6 · 2016: 7 · 2015: 7 · 2014: 6 · 2013: 7 · 2012: 13
- FWCI
- 2.82
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Research Portal (Queen's University Belfast) (submittedVersion)
- Funders
- GlaxoSmithKline
- Sanofi
- Cancer Research UK (A7261, A5862)
- National Cancer Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Keywords
- ADAM17, colorectal cancer, chemoresistance, 5-fluorouracil, transforming growth factor-alpha, amphiregulin, neuregulin-1, epidermal growth factor receptor, IGF-1 receptor, vascular endothelial growth factor receptor, apoptosis
- MeSH terms
- ADAM17 Protein, Animals, Antineoplastic Agents, Female, Fluorouracil, Humans, Ligands, Mice, Inbred BALB C, Neoplasm Transplantation, Transfection, Colorectal Neoplasms, Mice, SCID, Apoptosis, Drug Resistance, Neoplasm, Cell Line, Tumor, Cell Proliferation, Mice, ADAM Proteins, ErbB Receptors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
