Progranulin (PC-cell-derived growth factor/acrogranin) regulates invasion and cell survival.
Progranulin (pgrn; PC-cell-derived growth factor, epithelin precursor, or acrogranin) has been identified recently as an autocrine regulator of tumorigenesis in several cancer cells including SW-13 adrenal carcinomas and some breast cancers, but how pgrn promotes tumor progression is not well understood. SW-13 cells do not form tumors in nude mice but become highly tumorigenic when their pgrn expression is elevated, and this provides a useful model in which to investigate the role of pgrn in tumorigenesis. Here we show that, in SW-13 cells, the level of pgrn expression is a major determinant of the intrinsic activity of the mitogen-activated protein kinase, phosphatidylinositol 3'-kinase, and focal adhesion kinase signaling pathways. Pgrn stimulates the invasion of SW-13 cells across Matrigel-coated filters, increases the expression of matrix metalloproteinase 13 and 17, protects against anoikis, and overcomes the inhibition of cell growth imposed on SW-13 cells by interstitial type-I collagen. Inhibition of the mitogen-activated protein kinase and phosphatidylinositol 3'-kinase signaling pathways impairs each of the pgrn-dependent biological responses tested, but to different extents. The ability of pgrn to stimulate cell division, invasion, and survival demonstrates that pgrn regulates multiple steps in carcinomal progression, and suggests that the pgrn system may be a possible future therapeutic target.
D000310:Adrenal Gland Neoplasms / Q000201:enzymology / Q000473:pathology; D000818:Animals; D023102:Anoikis / Q000502:physiology*; D019556:COS Cells; D002455:Cell Division / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D003094:Collagen / Q000502:physiology; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006133:Growth Substances / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology; D020782:Matrix Metalloproteinases / Q000096:biosynthesis / Q000235:genetics; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology; D000077153:Progranulins; D011505:Protein-Tyrosine Kinases / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured
C492314:GRN protein, human; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D003094:Collagen; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D020782:Matrix Metalloproteinases