Cancer du sein et micro-environnement tumoral: rôle de la protéase ...

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Cathepsin-D, a key protease in breast cancer, is up-regulated in obese adiposetissue and controls adipogenesisOlivier Masson 1 , Christine Prébois 1 , Aline Meulle 2,3 , Cédric Dray 2,4 , DanielleDaviaud 2,4 , Didier Quilliot 5 , Philippe Valet 2,4 , Catherine Muller 3 , EmmanuelleLiaudet-Coopman 11 IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298,France; INSERM, U896, Montpellier, F-34298, France; Université Montpellier1,Montpellier, F-34298, France; CRLC Val dAurelle Paul Lamarque, Montpellier, F-34298, France. 2 Université de Toulouse, UPS, Institut de Médecine Moléculaire deRangueil, Equipe n°3, IFR31, Toulouse, France. 3 Institute of Pharmacology andStructural Biology CNRS UMR 5089, Toulouse, France; Université de Toulouse,Toulouse, France. 4 Institut National de la Santé et de la Recherche Médicale(INSERM), U858, Toulouse, France.5 Service de diabétologie, Maladiesmétaboliques et nutrition, CHU de Nancy, Hôpital J. dArc, 54201 Nancy Cedex,France.*Corresponding author: E Liaudet-Coopman, Inserm U896, IRCM Val d'Aurelle-Paul Lamarque, 34298 Montpellier Cedex 5, France ; Tel (33) 467 61 24 23 ; FAX(33) 467 31 37 87 ; E-mail: e.liaudet@valdorel.fnclcc.frRunning title: Role of cathepsin D in obesity and adipogenesisKeywords: cathepsin D, adipocyte, obesity, adipogenesis, differentiation, cancer1
ABSTRACTThe aspartic protease cathepsin-D (cath-D) is overexpressed by human epithelialbreast cancer cells and is closely correlated with poor prognosis in breast cancer.Adipocyte is one of the most prominent cell types in the tumor-microenvironment ofbreast cancers and clinical studies pointed out that obesity increases the incidence ofbreast cancer. Here, we provide the first evidence that cath-D expression is upregulatedin adipose tissue of obese human as well as in adipocytes of obeseC57BI6/J mouse model. Cath-D expression is also increased during human andmouse adipocyte differentiation. We demonstrate that cath-D silencing in NIH-3T3F442A murine preadipocytes significantly inhibits the expression of PPARg, HSLand aP2 adipocyte differentiation markers after adipogenesis induction, and leads tolipid-depleted cells. This study highlights the key role of cath-D in the control ofadipogenesis, and suggests that this protease may be a novel target in obesity.Since cath-D is implicated in breast cancer progression, we propose that cath-D mayrepresent a molecular link between cancer and obesity.2
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Université Montpellier I UFR Méd
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Un grand merci à tous mes collabor
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TitleBreast cancer and tumoral micr
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Cancer du sein et micro-environneme
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C. PRESENTATION DU TRAVAIL DE THESE
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But de la thèseLa cathepsine-D (ca
Page 13 and 14: I. Le tissu adipeux1) Généralité
Page 15 and 16: (Adenosine triphosphate). Cette pro
Page 18 and 19: Cette synthèse de novo a lieu dans
Page 20 and 21: ABFigure 6 : Schéma de la oxydati
Page 22 and 23: d. Ladipocyte : une cellule sécré
Page 24 and 25: 3) Ladipogenèsea. Les différentes
Page 26 and 27: . Les facteurs de transcriptionLa d
Page 28 and 29: Lexpression de C/EBP est quant à e
Page 30 and 31: adipeux. Les analyses histologiques
Page 32 and 33: adipocyteFigure 10 : Schéma repré
Page 34 and 35: II. La cathepsine-D1) Synthèse, ma
Page 36 and 37: les cath-B et L, en une forme matur
Page 38 and 39: Il existe deux RM6P : le RM6P/IGFII
Page 40 and 41: 2) Fonctions de la cath-Da. Dans la
Page 42 and 43: . Dans les pathologiesEn plus de se
Page 44 and 45: c. Rôles et mécanismes daction da
Page 46 and 47: carcinome de prostate serait respon
Page 48 and 49: La cath-D joue donc un rôle import
Page 50 and 51: Une fois le marquage des peptides e
Page 52 and 53: Afin de réaliser ce projet, nous a
Page 54 and 55: III. Le récepteur LRP11) Organisat
Page 56 and 57: 2) Trafic intra-cellulaireComme le
Page 58 and 59: LRP1αLRP1Membrane associatedprotea
Page 60 and 61: Tableau 3 : Ligands connus du LRP1(
Page 62 and 63: I. Etude du rôle de la cathepsine
Page 66 and 67: IntroductionConsumption of meals ri
Page 68 and 69: (Fig. 1A, panel a). This differenti
Page 70 and 71: differentiated adipocyte (Fig. 4B).
Page 72 and 73: DiscussionOur results demonstrate t
Page 74 and 75: from normal and peri-al breast adip
Page 76 and 77: mouse RS9 (sens 5CGGCCCGGGAGCTGTTGA
Page 78 and 79: agreement of local ethic committee.
Page 80 and 81: Statistical analysis. Results are e
Page 82 and 83: Loncarek J, Freiss G, Vignon F and
Page 84 and 85: Aa3000 *b4000*B8000**cath-D mRNA(ar
Page 86 and 87: ABcath-D mRNA(ratio RS9)PPARg mRNA(
Page 88 and 89: A D3 D7 D14D0BaD0 D3 D7 D14D0 D3 D7
Page 90 and 91: AshLucshcath-DF442A C34 C37 A4 D10c
Page 92 and 93: AF442-AC34C37A4D10BF442-AC34C37A4D1
Page 94 and 95: II. Etude du rôle du LRP1 dans les
Page 96 and 97: 2) Article 2:LRP1 receptor controls
Page 98 and 99: LRP1, Adipogenesis, Obesityrelative
Page 100 and 101: LRP1, Adipogenesis, ObesityFigure 3
Page 102 and 103: LRP1, Adipogenesis, ObesityFigure 5
Page 104 and 105: LRP1, Adipogenesis, ObesitySome ins
Page 106 and 107: LRP1, Adipogenesis, ObesityLipolysi
Page 108 and 109: CONCLUSIONLa cathepsine D (cath-D)
Page 110 and 111: la souris obèses. Enfin, linhibiti
Page 112 and 113: carcinogénique sont encore mal con
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Ce travail de thèse a étudié, po
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REFERENCESAhima, R. S. (2006). Adip
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implicates them as antigen presenti
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Cataldo, A. M., Barnett, J. L., Ber
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Folkman, J. (2003). Fundamental con
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Hofmann, S. M., Zhou, L., Perez-Til
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Langin, D. (2006a). Adipose tissue
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Ludwig, T., Ovitt, C. E., Bauer, U.
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Nirde, P., Derocq, D., Maynadier, M
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Rozanov, D. V., Hahn-Dantona, E., S
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Taleb, S., Cancello, R., Clement, K
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Xiao, Y., Junfeng, H., Tianhong, L.
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F. ANNEXE98
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Cathepsin D is a new ligand for ext
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INTRODUCTIONLysosomal aspartic prot
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pcDNA3.1(+)Myc-tagged LRP1b into pc
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(Protein refolding kit, Novagen) fo
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anti-mouse-gold (Aurion). Sections
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not secrete detectable levels of pr
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using cath-D-/- MEF transfected wit
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co-culture outgrowth assays with ca
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REFERENCES1. Vignon, F., Capony, F.
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steps in vivo: proliferation, angio
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28. Laurent-Matha, V., Lucas, A., H
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42. Zurhove, K., Nakajima, C., Herz
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Figure 1. Cath-D interacts with the
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Figure 2. Cath-D binds to residues
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Figure 3. Cath-D interacts with LRP
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Figure 5. Silencing LRP1 in cath-D
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Figure 1. Cath-D interacts with the
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Figure 6. LRP1 is the receptor medi
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Beaujouin, Figure Sup. 2cath-D-/-ME
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RésuméLaspartyl protéase catheps
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