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Targeting the sheddase activity of Adam17 by an Anti-ADAM17 antibody D1(A12) inhibits head and neck squamous cell carcinoma cell proliferation and motility via blockage of bradykinin induced HERs transactivation
Huang Y.4; Benaich N.4; Tape C.4; Kwok H.F.4; Murphy G.4
2014-06-21
Source PublicationInternational Journal of Biological Sciences
ISSN14492288
Volume10Issue:7Pages:702-714
Abstract

A disintegrin and metalloproteinase 17 (ADAM17) regulates key cellular processes including proliferation and migration through the shedding of a diverse array of substrates such as epidermal growth factor receptor (EGFR) ligands. ADAM17 is implicated in the pathogenesis of many diseases including rheumatoid arthritis and cancers such as head and neck squamous cell carcinoma (HNSCC). As a central mediator of cellular events, overexpressed EGFR is a validated molecular target in HNSCC. However, EGFR inhibition constantly leads to tumour resistance. One possible mechanism of resistance is the activation of alternative EGFR family receptors and downstream pathways via the release of their ligands. Here, we report that treating human HNSCC cells in vitro with a human anti-ADAM17 inhibitory antibody, D1(A12), suppresses proliferation and motility in the absence or presence of the EGFR tyrosine kinase inhibitor (TKI) gefitinib. Treatment with D1(A12) decreases both the endogenous and the bradykinin (BK)-stimulated shedding of HER ligands, accompanied by a reduction in the phosphorylation of HER receptors and downstream signalling pathways including STAT3, AKT and ERK. Knockdown of ADAM17, but not ADAM10, also suppresses HNSCC cell proliferation and migration. Furthermore, we show that heregulin (HRG) and heparin-binding epidermal growth factor like growth factor (HB-EGF) predominantly participate in proliferation and migration, respectively. Taken together, these results demonstrate that D1(A12)-mediated inhibition of cell proliferation, motility, phosphorylation of HER receptors and downstream signalling is achieved via reduced shedding of ADAM17 ligands. These findings underscore the importance of ADAM17 and suggest that D1(A12) might be an effective targeted agent for treating EGFR TKI-resistant HNSCC. © Ivyspring International Publisher.

KeywordAdam17 Cell Proliferation And Motility Her Receptor And ligAnds Inhibitory Antibody
DOI10.7150/ijbs.9326
URLView the original
Indexed BySCI
Language英语
WOS Research AreaBiochemistry & Molecular Biology ; Life Sciences & Biomedicine - Other Topics
WOS SubjectBiochemistry & Molecular Biology ; Biology
WOS IDWOS:000339317100005
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Cited Times [WOS]:18   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
Affiliation1.IONTAS Ltd
2.Guy's and St Thomas' NHS Foundation Trust
3.Universidade de Macau
4.University of Cambridge
5.The Institute of Cancer Research, London
Recommended Citation
GB/T 7714
Huang Y.,Benaich N.,Tape C.,et al. Targeting the sheddase activity of Adam17 by an Anti-ADAM17 antibody D1(A12) inhibits head and neck squamous cell carcinoma cell proliferation and motility via blockage of bradykinin induced HERs transactivation[J]. International Journal of Biological Sciences,2014,10(7):702-714.
APA Huang Y.,Benaich N.,Tape C.,Kwok H.F.,&Murphy G..(2014).Targeting the sheddase activity of Adam17 by an Anti-ADAM17 antibody D1(A12) inhibits head and neck squamous cell carcinoma cell proliferation and motility via blockage of bradykinin induced HERs transactivation.International Journal of Biological Sciences,10(7),702-714.
MLA Huang Y.,et al."Targeting the sheddase activity of Adam17 by an Anti-ADAM17 antibody D1(A12) inhibits head and neck squamous cell carcinoma cell proliferation and motility via blockage of bradykinin induced HERs transactivation".International Journal of Biological Sciences 10.7(2014):702-714.
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