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.
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.
Monami
Giada
G
Department of Urology, Anatomy and Cell Biology and Cellular Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Gonzalez
Eva M
EM
Hellman
Michelle
M
Gomella
Leonard G
LG
Baffa
Raffaele
R
Iozzo
Renato V
RV
Morrione
Andrea
A
D002295:Carcinoma, Transitional Cell / Q000201:enzymology / Q000473:pathology*; D002465:Cell Movement / Q000502:physiology*; D004789:Enzyme Activation; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism* / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D051419:Paxillin / Q000378:metabolism*; D000077153:Progranulins; D011498:Protein Precursors / Q000378:metabolism / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D001749:Urinary Bladder Neoplasms / Q000201:enzymology / Q000473:pathology*
C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D051419:Paxillin; D000077153:Progranulins; D011498:Protein Precursors; D011994:Recombinant Proteins; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3