Matrix Metalloproteinase-7 Facilitates Insulin-Like Growth Factor Bioavailability through Its Proteinase Activity on Insulin-Like Growth Factor Binding Protein 3

Matrix metalloproteinase-7 (MMP-7) secreted by cancer cells has been implicated classically in the basement membrane destruction associated with tumor cell invasion and metastasis. Recent epidemiologic studies have established a correlation between high levels of circulating insulinlike growth factor (IGF) and low levels of IGF binding protein 3 (IGFBP3), and relative risk of developing colon, breast, prostate, and lung cancer, which are known to produce MMP-7. In this study, IGFBP-3 was assessed as a candidate for the physiologic substrate of MMP-7. MMP-7 proteolysis generated four major fragments (26 kDa, 17 kDa, 15.5 kDa, and 15.5 kDa), and two cleavage sites were identified: one at the site of hydrolysis of the K-I peptide bond and one at the R-L peptide bond. The former site is different from the previously reported site of cleavage of IGFBP-3 by other proteases. Addition of IGFBP-3 inhibited IGF-I-mediated IGF type 1 receptor (IGF-IR) phosphorylation and activation of the downstream molecule Akt in BALB/c 3T3 fibroblasts overexpressing human IGF-IR (3T3-IGF-IR) and in two human colon cancer cell lines (COLO201 and HT29). Coincubation of the IGF-I/IGFBP-3 complex with MMP-7 restored IGF-I-mediated IGF-IR phosphorylation and activation of Akt in these cell lines. The IGF-I signal recovered by MMP-7 protected against apoptosis induced by anoikis in 3T3-IGF-IR cells. These results indicate that MMP-7 proteolysis of IGFBP-3 plays a crucial role in regulating IGF-I bioavailability, thereby promoting cell survival. This mechanism may contribute to the tumorigenesis of MMP-7-producing IGF-IR-expressing tumors in the primary site and to organ-specific metastasis in a paracrine manner.

[1]  Takanori Aoki,et al.  Matrix Metalloproteinases Cleave Connective Tissue Growth Factor and Reactivate Angiogenic Activity of Vascular Endothelial Growth Factor 165* , 2002, The Journal of Biological Chemistry.

[2]  P. Glazer,et al.  IGF1 Receptor Expression Protects against Microenvironmental Stress Found in the Solid Tumor , 2002, Radiation research.

[3]  L. Matrisian,et al.  Osteopontin, a Novel Substrate for Matrix Metalloproteinase-3 (Stromelysin-1) and Matrix Metalloproteinase-7 (Matrilysin)* , 2001, The Journal of Biological Chemistry.

[4]  T. Rohan,et al.  Role of the insulin-like growth factor family in cancer development and progression. , 2000, Journal of the National Cancer Institute.

[5]  P. Cohen,et al.  Role of insulin‐like growth factors and their binding proteins in growth control and carcinogenesis , 2000, Journal of cellular physiology.

[6]  B. Fingleton,et al.  The metalloproteinase matrilysin proteolytically generates active soluble Fas ligand and potentiates epithelial cell apoptosis , 1999, Current Biology.

[7]  T. Yeatman,et al.  Expression of insulin-like growth factor-1 receptor in human colorectal cancer. , 1999, Human pathology.

[8]  Y. Okada,et al.  Contribution of matrilysin (MMP-7) to the metastatic pathway of human colorectal cancers , 1999, Gut.

[9]  C. Martínez-A,et al.  The Matrix Metalloproteinase-9 Regulates the Insulin-like Growth Factor-triggered Autocrine Response in DU-145 Carcinoma Cells* , 1999, The Journal of Biological Chemistry.

[10]  P. Clayton,et al.  Insulin-like growth factor I, IGF binding protein 3, and IGFBP protease activity: relation to anthropometric indices in solid tumours or leukaemia , 1999, Archives of disease in childhood.

[11]  M. Spitz,et al.  Plasma levels of insulin-like growth factor-I and lung cancer risk: a case-control analysis. , 1999, Journal of the National Cancer Institute.

[12]  G. Kulik,et al.  Akt-Dependent and -Independent Survival Signaling Pathways Utilized by Insulin-Like Growth Factor I , 1998, Molecular and Cellular Biology.

[13]  M. Baciuchka,et al.  Insulin‐like growth factor (IGF)–binding protein‐3 (IGFBP‐3) proteolysis in patients with colorectal cancer: possible association with the metastatic potential of the tumor , 1998, International journal of cancer.

[14]  Sandra,et al.  A dominant negative mutant of the insulin-like growth factor-I receptor inhibits the adhesion, invasion, and metastasis of breast cancer. , 1998, Cancer research.

[15]  S. Nicosia,et al.  AKT2, a member of the protein kinase B family, is activated by growth factors, v-Ha-ras, and v-src through phosphatidylinositol 3-kinase in human ovarian epithelial cancer cells. , 1998, Cancer research.

[16]  M. Stampfer,et al.  Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. , 1998, Science.

[17]  T. Ishikawa,et al.  Matrilysin‐specific antisense oligonucleotide inhibits liver metastasis of human colon cancer cells in a nude mouse model , 1998, International journal of cancer.

[18]  M. Barbacid,et al.  Identification of Insulin-like Growth Factor-binding Protein-1 as a Potential Physiological Substrate for Human Stromelysin-3* , 1997, The Journal of Biological Chemistry.

[19]  M. Binoux,et al.  Proteolytic fragments of insulin-like growth factor binding protein-3: N-terminal sequences and relationships between structure and biological activity. , 1997, Comptes rendus de l'Academie des sciences. Serie III, Sciences de la vie.

[20]  H. Yamamoto,et al.  Relation of enhanced secretion of active matrix metalloproteinases with tumor spread in human hepatocellular carcinoma. , 1997, Gastroenterology.

[21]  Y. Okada,et al.  Degradation of decorin by matrix metalloproteinases: identification of the cleavage sites, kinetic analyses and transforming growth factor-beta1 release. , 1997, The Biochemical journal.

[22]  A. Klippel,et al.  Antiapoptotic signalling by the insulin-like growth factor I receptor, phosphatidylinositol 3-kinase, and Akt , 1997, Molecular and cellular biology.

[23]  B. Hogan,et al.  Intestinal tumorigenesis is suppressed in mice lacking the metalloproteinase matrilysin. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[24]  M. Rubini,et al.  The IGF-I receptor in mitogenesis and transformation of mouse embryo cells: role of receptor number. , 1997, Experimental cell research.

[25]  P. Cohen,et al.  Mechanism of activation of protein kinase B by insulin and IGF‐1. , 1996, The EMBO journal.

[26]  T. Ishikawa,et al.  Matrilysin is associated with progression of colorectal tumor. , 1996, Cancer letters.

[27]  J. Massagué,et al.  Diverse Cell Surface Protein Ectodomains Are Shed by a System Sensitive to Metalloprotease Inhibitors (*) , 1996, The Journal of Biological Chemistry.

[28]  John M. Whitelock,et al.  The Degradation of Human Endothelial Cell-derived Perlecan and Release of Bound Basic Fibroblast Growth Factor by Stromelysin, Collagenase, Plasmin, and Heparanases (*) , 1996, The Journal of Biological Chemistry.

[29]  L. Matrisian,et al.  Matrilysin: an epithelial matrix metalloproteinase with potentially novel functions. , 1996, The international journal of biochemistry & cell biology.

[30]  S. Chandler,et al.  Matrix metalloproteinases degrade myelin basic protein , 1995, Neuroscience Letters.

[31]  K. Suzuki,et al.  Characterization of insulin-like growth factor-binding protein 5-degrading proteases produced throughout murine osteoblast differentiation. , 1995, Endocrinology.

[32]  C Haanen,et al.  A novel assay for apoptosis. Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labelled Annexin V. , 1995, Journal of immunological methods.

[33]  K. Imai,et al.  Matrix Metalloproteinase 7 (Matrilysin) from Human Rectal Carcinoma Cells , 1995, The Journal of Biological Chemistry.

[34]  R. Baserga,et al.  Loss of the metastatic phenotype in murine carcinoma cells expressing an antisense RNA to the insulin-like growth factor receptor. , 1995, Cancer research.

[35]  D. Clemmons,et al.  Insulin-like growth factors and their binding proteins: biological actions. , 1995, Endocrine reviews.

[36]  R. Senior,et al.  Matrilysin is much more efficient than other matrix metalloproteinases in the proteolytic inactivation of alpha 1-antitrypsin. , 1994, Biochemical and biophysical research communications.

[37]  K. Suzuki,et al.  Matrix metalloproteinases degrade insulin-like growth factor-binding protein-3 in dermal fibroblast cultures. , 1994, The Journal of biological chemistry.

[38]  A. H. Drummond,et al.  Processing of tumour necrosis factor-α precursor by metalloproteinases , 1994, Nature.

[39]  Jack P. Witty,et al.  Expression and localization of matrix‐degrading metalloproteinases during colorectal tumorigenesis , 1994, Molecular carcinogenesis.

[40]  J. Nip,et al.  Paracrine growth stimulation by hepatocyte-derived insulin-like growth factor-1: a regulatory mechanism for carcinoma cells metastatic to the liver. , 1994, Cancer research.

[41]  Motoharu Seiki,et al.  A matrix metalloproteinase expressed on the surface of invasive tumour cells , 1994, Nature.

[42]  R. Rosenfeld,et al.  Insulin-Like Growth Factor Binding Protein-3 Concentrations and Insulin-Like Growth Factor Binding Protein-3 Protease Activity in Sera of Patients with Malignant Solid Tumors or Leukemia , 1994, Pediatric Research.

[43]  M. Wardell,et al.  Proteolysis of human native and oxidised α1-proteinase inhibitor by matrulysin and stromelysin , 1994 .

[44]  H. Birkedal‐Hansen,et al.  Comparative sequence specificities of human 72- and 92-kDa gelatinases (type IV collagenases) and PUMP (matrilysin). , 1993, Biochemistry.

[45]  J. M. Ryan,et al.  The matrix metalloproteinase pump-1 catalyzes formation of low molecular weight (pro)urokinase in cultures of normal human kidney cells. , 1992, The Journal of biological chemistry.

[46]  J. Abecassis,et al.  Expression of collagenase‐related metalloproteinase genes in human lung or head and neck tumours , 1991, International journal of cancer.

[47]  P. Chambon,et al.  A novel metalloproteinase gene specifically expressed in stromal cells of breast carcinomas , 1990, Nature.

[48]  H. Yasumitsu,et al.  Purification and characterization of extracellular matrix-degrading metalloproteinase, matrin (pump-1), secreted from human rectal carcinoma cell line. , 1990, Cancer research.

[49]  J. Woessner,et al.  Purification and properties of a small latent matrix metalloproteinase of the rat uterus. , 1988, The Journal of biological chemistry.

[50]  M. Brawer,et al.  Expression of metalloproteinase genes in human prostate cancer , 2005, Journal of Cancer Research and Clinical Oncology.

[51]  M. Mareel,et al.  Release of an invasion promoter E-cadherin fragment by matrilysin and stromelysin-1. , 2001, Journal of cell science.

[52]  A. Hassan,et al.  Insulin-like growth factor II supply modifies growth of intestinal adenoma in Apc(Min/+) mice. , 2000, Cancer research.

[53]  M. Imamura,et al.  Possible paracrine mechanism of insulin‐like growth factor‐2 in the development of liver metastases from colorectal carcinoma , 1999, Cancer.

[54]  Stampfer,et al.  Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3. , 1999, Journal of the National Cancer Institute.

[55]  P. Bang.  Serum proteolysis of IGFBP-3. , 1995, Progress in growth factor research.

[56]  H. Birkedal‐Hansen.  Proteolytic remodeling of extracellular matrix. , 1995, Current opinion in cell biology.

[57]  K. Mimori,et al.  Overexpression of matrix metalloproteinase‐7 mRNA in human colon carcinomas , 1995, Cancer.

[58]  R. Baxter,et al.  The role of glycosylation in the action of IGFBP-3. , 1995, Progress in growth factor research.

[59]  D. Leroith,et al.  Insulin-like Growth Factors and Cancer , 1995, Annals of Internal Medicine.

[60]  L. Matrisian,et al.  Expression and localization of the matrix metalloproteinase pump‐1 (MMP‐7) in human gastric and colon carcinomas , 1991, Molecular carcinogenesis.