PloS one, 2015-03, Vol.10 (3), p.e0116006-e0116006
2015
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- Autor(en) / Beteiligte
- Titel
- A membrane-type-1 matrix metalloproteinase (MT1-MMP)-discoidin domain receptor 1 axis regulates collagen-induced apoptosis in breast cancer cells
- Ist Teil von
- PloS one, 2015-03, Vol.10 (3), p.e0116006-e0116006
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2015
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- During tumour dissemination, invading breast carcinoma cells become confronted with a reactive stroma, a type I collagen-rich environment endowed with anti-proliferative and pro-apoptotic properties. To develop metastatic capabilities, tumour cells must acquire the capacity to cope with this novel microenvironment. How cells interact with and respond to their microenvironment during cancer dissemination remains poorly understood. To address the impact of type I collagen on the fate of tumour cells, human breast carcinoma MCF-7 cells were cultured within three-dimensional type I collagen gels (3D COL1). Using this experimental model, we have previously demonstrated that membrane type-1 matrix metalloproteinase (MT1-MMP), a proteinase overexpressed in many aggressive tumours, promotes tumour progression by circumventing the collagen-induced up-regulation of BIK, a pro-apoptotic tumour suppressor, and hence apoptosis. Here we performed a transcriptomic analysis to decipher the molecular mechanisms regulating 3D COL1-induced apoptosis in human breast cancer cells. Control and MT1-MMP expressing MCF-7 cells were cultured on two-dimensional plastic plates or within 3D COL1 and a global transcriptional time-course analysis was performed. Shifting the cells from plastic plates to 3D COL1 activated a complex reprogramming of genes implicated in various biological processes. Bioinformatic analysis revealed a 3D COL1-mediated alteration of key cellular functions including apoptosis, cell proliferation, RNA processing and cytoskeleton remodelling. By using a panel of pharmacological inhibitors, we identified discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase specifically activated by collagen, as the initiator of 3D COL1-induced apoptosis. Our data support the concept that MT1-MMP contributes to the inactivation of the DDR1-BIK signalling axis through the cleavage of collagen fibres and/or the alteration of DDR1 receptor signalling unit, without triggering a drastic remodelling of the transcriptome of MCF-7 cells.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0116006Titel-ID: cdi_plos_journals_1663912132
- Format
- –
- Schlagworte
- Apoptosis, Apoptosis - drug effects, Apoptosis Regulatory Proteins - metabolism, Biological activity, Breast cancer, Breast carcinoma, Breast Neoplasms - pathology, Cancer, Cancer cells, Cell adhesion & migration, Cell Cycle - drug effects, Cell Line, Tumor, Cell proliferation, Collagen, Collagen (type I), Collagen Type I - chemistry, Collagen Type I - pharmacology, Cytoskeleton, Cytoskeleton - drug effects, Cytoskeleton - metabolism, Deactivation, Developmental biology, Discoidin Domain Receptors, Fibers, Gels, Gene expression, Gene Expression Regulation, Neoplastic - drug effects, Human health sciences, Humans, Inactivation, Kinases, Laboratories, Matrix metalloproteinase, Matrix Metalloproteinase 14 - genetics, Matrix Metalloproteinase 14 - metabolism, Membrane Proteins - metabolism, Metalloproteinase, Metastases, Metastasis, Molecular modelling, Morphogenesis, Oncologie, Oncology, Pharmacology, Plastic plates, Plastics, Protein-tyrosine kinase receptors, Proteinase, Receptor Protein-Tyrosine Kinases - metabolism, Receptors, Mitogen - metabolism, Ribonucleic acid, RNA, RNA processing, RNA Processing, Post-Transcriptional - drug effects, Sciences de la santé humaine, Signaling, Stroma, Three dimensional models, Transcription, Transcriptome - drug effects, Tumor Microenvironment - drug effects, Tumors, Tyrosine