Proepithelin Promotes Migration and Invasion of 5637 Bladder Cancer Cells through the Activation of ERK1/2 and the Formation of a Paxillin/FAK/ERK Complex

Abstract

The growth factor proepithelin (also known as progranulin, acrogranin, PC-derived growth factor, or granulin-epithelin precursor) is a secreted glycoprotein that functions as an important regulator of cell growth, migration, and transformation. Proepithelin is overexpressed in a great variety of cancer cell lines and clinical specimens of breast, ovarian, and renal cancer as well as glioblastomas. In this study, we have investigated the effects of proepithelin on bladder cancer cells using human recombinant proepithelin purified to homogeneity from 293-EBNA cells. Although proepithelin did not appreciably affect cell growth, it did promote migration of 5637 bladder cancer cells and stimulate in vitro wound closure and invasion. These effects required the activation of the mitogen-activated protein kinase pathway and paxillin, which upon proepithelin stimulation formed a complex with focal adhesion kinase and active extracellular signal-regulated kinase. Our results provide the first evidence for a role of proepithelin in stimulating migration and invasion of bladder cancer cells, and support the hypothesis that this growth factor may play a critical role in the establishment of the invasive phenotype. (Cancer Res 2006; 66(14): 7103-10)

The granulin gene family: from cancer to dementia

“…Of equal importance to the problems that accrue when PGRN levels are low is what happens to cells with increased exposure to PGRN. Elevated PGRN stimulates proliferation, (8)(9)(10)15,16,28,40) survival, (9,21,74) and motility (9,24,28) of epithelia, fibroblasts, and endothelia. PGRN activates typical growth factor signal transduction pathways such as the phosphorylation of shc and p44/42 mitogen-activated protein kinase (p44/42MAPK) in the extracellular regulated kinase (ERK) pathway as well as phosphatidylinositol 3-kinase (PI3K), protein kinase B/AKT, and the p70 S6 kinase in the PI3K pathway.…”

“…(81) FAK provides a link between integrin and growth factor signaling since it is required for epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) to promote cell motility. (82) In bladder cancer cells where PGRN is a strong motogen but a poor mitogen, PGRN promoted the association of FAK with paxillin and p44/42MAPK, (24) suggesting, at the very least, a cellular link between PGRN and extracellular matrix (ECM) signaling machinery.…”

“…(6,7) The role of PGRN in cancer has been repeatedly demonstrated. (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26) PGRN has been invoked in early embryogenesis, (27) wound repair, and inflammation. (28)(29)(30) These are diverse roles, extending from control of embryonic development during the first days of life to the survival of long-lived post-mitotic neurons of the adult brain.…”

Epithelial–mesenchymal transition in malignant mesothelioma

“…After 24 h, the cells in the upper chamber were removed, whereas the cells that migrated to the lower chamber were counted under the microscope after fixing and staining in Coomassie blue solution, as described. 34,35 …”

“…34,35 Briefly, cells were starved of serum for 24 h, then seeded in triplicate (10 3 in 200 ml) in Boyden chambers (upper chamber) (BD Biosciences). Lower chambers contained 500 ml of SFM or 500 ml of medium supplemented with 10% fetal bovine serum.…”