Overexpression of the autocrine motility factor/phosphoglucose isomerase induces transformation and survival of NIH-3T3 fibroblasts.
Autocrine motility factor (AMF)/phosphoglucose isomerase (PGI) is a ubiquitous cytosolic enzyme and is produced as a leaderless secretory protein, released from cells via a nonclassical pathway. AMF/PGI acts extracellularly as a potent mitogen/cytokine (CXXC, chemokine). Increased expression of AMF/PGI and its receptor/CXXC-R has been found in a wide spectrum of malignancies, and is associated with cancer progression and metastasis. To directly elucidate the functional role of AMF/PGI on cell motility and neoplastic transformation, we stably transfected AMF/PGI cDNA into NIH-3T3 cells. Ectopic overexpression of AMF/PGI results in its secretion and activation via a constitutive autocrine activation loop that renders the cells highly motile, acquiring a transformed phenotype in vitro and tumorigenicity in vivo. The transformed phenotype of AMF/PGI-transfected cells leads in part resistance to induction of apoptosis induced by serum starvation, through the activation of phosphatidylinositol 3'-kinase/Akt signaling pathway and down-regulation of caveolin-1 expression. Overexpression of this housekeeping gene induces resistance to apoptosis and neoplastic transformation, and, thus, AMF/PGI represents a novel class of oncogenic protein.
Tsutsumi
Soichi
S
Tumor Progression and Metastasis, Karmanos Cancer Institute, Department of Pathology, Wayne State University, Medical School, Detroit, Michigan 48201, USA.
Hogan
Victor
V
Nabi
Ivan R
IR
Raz
Avraham
A
D016475:3T3 Cells; D000818:Animals; D002455:Cell Division; D002470:Cell Survival / Q000502:physiology*; D002471:Cell Transformation, Neoplastic; D016895:Culture Media, Serum-Free; D005347:Fibroblasts / Q000166:cytology; D005354:Fibrosarcoma / Q000235:genetics / Q000473:pathology*; D005956:Glucose-6-Phosphate Isomerase / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D010641:Phenotype; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection
D016895:Culture Media, Serum-Free; D011994:Recombinant Proteins; D005956:Glucose-6-Phosphate Isomerase