title: Elastin-derived peptides increase invasive capacities of lung cancer cells by post-transcriptional regulation of MMP-2 and uPA.
abstract: Elastin-rich lung extracellular matrix is largely remodeled during tumor invasion. Elastin degradation produces peptides displaying a wide range of biological activities. These elastin derived peptides (EP) interact with the elastin receptor complex (ERC) but also bind to α(V)β(3) integrin and galectin-3. In this study, we explored the role of EP and their receptors in tumor progression of lung carcinomas. Non-invasive and invasive lung tumor cell lines were incubated in presence of kappa-elastin (κE) or with synthetic peptides displaying receptor-specific sequences (VGVAPG, GRKRK, AGVPGLGVG and AGVPGFGAG). Modified Boyden chamber assays revealed an increased invasive capacity of invasive cells induced by κE. EP treatment had no effect on cell proliferation but zymography analysis revealed an increase of pro-MMP-2 and uPA levels in the conditioned media of treated cells. Moreover, the active form of MMP-2 was increased in invasive cells. Interestingly, this regulation was not observed at the mRNA level and actinomycin D was unable to inhibit κE effects. We also observed that the regulation of proteases protein level following κE treatment was an early process detectable after 1 h. All these effects could not be inhibited by lactose and V14, two ERC antagonists, or by blocking antibodies against α(V)β(3) integrin and galectin-3. Finally, VGVAPG and GRKRK failed to reproduce κE effects whereas nonapeptides partially mimicked them. These results demonstrate that treatment with EP up-regulates invasiveness of lung tumor cells via the release of proteolytic enzymes. This modulation involves post-transcriptional mechanisms and a nonapeptide-receptor different from the ERC, α(V)β(3) integrin and galectin-3.
authors.affiliation: INSERM, UMRS 903, IFR53, Université de Reims Champagne-Ardenne, Reims, France.
authors.forename: Simon
authors.initials: S
authors.lastname: Toupance
authors.forename: Bertrand
authors.initials: B
authors.lastname: Brassart
authors.forename: Fanja
authors.initials: F
authors.lastname: Rabenoelina
authors.forename: Christelle
authors.initials: C
authors.lastname: Ghoneim
authors.forename: Laurent
authors.initials: L
authors.lastname: Vallar
authors.forename: Myriam
authors.initials: M
authors.lastname: Polette
authors.forename: Laurent
authors.initials: L
authors.lastname: Debelle
authors.forename: Philippe
authors.initials: P
authors.lastname: Birembaut
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002465:Cell Movement; D049109:Cell Proliferation; D004549:Elastin / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D037502:Galectin 3 / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D009842:Oligopeptides / Q000494:pharmacology*; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics* / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D037502:Galectin 3; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D012333:RNA, Messenger; D004549:Elastin; D014568:Urokinase-Type Plasminogen Activator; D020778:Matrix Metalloproteinase 2