title: ADAM12 redistributes and activates MMP-14, resulting in gelatin degradation, reduced apoptosis and increased tumor growth.
abstract: Matrix metalloproteinases (MMPs), in particular MMP-2, MMP-9 and MMP-14, play a key role in various aspects of cancer pathology. Likewise, ADAMs (a disintegrin and metalloproteinases), including ADAM12, are upregulated in malignant tumors and contribute to the pathology of cancers. Here, we show that there is a positive correlation between MMP-14 and ADAM12 expression in human breast cancer. We demonstrated that in 293-VnR and human breast cancer cells expressing ADAM12 at the cell surface, endogenous MMP-14 was recruited to the cell surface, resulting in its activation. Subsequent to this activation, gelatin degradation was stimulated and tumor cell apoptosis was decreased, with reduced expression of the pro-apoptotic proteins BCL2L11 and BIK. The effect on gelatin degradation was abrogated by inhibition of the MMP-14 activity and appeared to be dependent on cell surface αVβ3 integrin localization, but neither the catalytic activity of ADAM12 nor the cytoplasmic tail of ADAM12 were required. The significance of ADAM12-induced activation of MMP-14 was underscored by a reduction in MMP-14-mediated gelatin degradation and abolition of apoptosis-protective effects by specific monoclonal antibodies against ADAM12. Furthermore, orthotopic implantation of ADAM12-expressing MCF7 cells in nude mice produced tumors with increased levels of activated MMP-14 and confirmed that ADAM12 protects tumor cells against apoptosis, leading to increased tumor progression. In conclusion, our data suggest that a ternary protein complex composed of ADAM12, αVβ3 integrin and MMP-14 at the tumor cell surface regulates the function of MMP-14. This interaction might point to a novel concept for the development of MMP-14-targeting drugs in treating cancer.
authors.affiliation: Department of Biomedical Sciences and Biotech Research and Innovation Centre (BRIC), University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Reidar
authors.initials: R
authors.lastname: Albrechtsen
authors.forename: Marie
authors.initials: M
authors.lastname: Kveiborg
authors.forename: Dorte
authors.initials: D
authors.lastname: Stautz
authors.forename: Jonas
authors.initials: J
authors.lastname: Vikeså
authors.forename: Julie B
authors.initials: JB
authors.lastname: Noer
authors.forename: Alexander
authors.initials: A
authors.lastname: Kotzsh
authors.forename: Finn Cilius
authors.initials: FC
authors.lastname: Nielsen
authors.forename: Ulla M
authors.initials: UM
authors.lastname: Wewer
authors.forename: Camilla
authors.initials: C
authors.lastname: Fröhlich
mesh_terms: D051722:ADAM Proteins / Q000276:immunology / Q000378:metabolism*; D000072199:ADAM12 Protein; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology*; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D005260:Female; D005780:Gelatin / Q000378:metabolism*; D057809:HEK293 Cells; D064593:Heterografts; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D061986:MCF-7 Cells; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD
chemical_list: D000911:Antibodies, Monoclonal; D039302:Integrin alphaVbeta3; D008565:Membrane Proteins; D005780:Gelatin; D051722:ADAM Proteins; D000072199:ADAM12 Protein; C000606480:ADAM12 protein, human; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14
keywords: ADAM12; Apoptosis; Gelatin degradation; MMP-14; αVβ3 integrin