Galectin-1 is a novel functional receptor for tissue plasminogen activator in pancreatic cancer.
OBJECTIVE
Tissue plasminogen activator (tPA) exerts many different functions in addition to its role in fibrinolysis. In pancreatic ductal adenocarcinoma (PDA), tPA is overexpressed and plays an important role in proliferation, invasion, and angiogenesis. tPA interaction with cell membrane receptors has been related to increased proteolytic activity and to signal transduction through nonenzymatic mechanisms. The aim was to analyze the role of galectin-1 (Gal-1), an endogenous lectin that also is overexpressed in PDA, as a new functional receptor for tPA.


METHODS
Gal-1/tPA interaction was analyzed using surface plasmon resonance and pull-down assays. Pancreatic cells and tumors were used to study Gal-1 expression and localization by Western blot and immunostaining. Down-regulation of Gal-1 by small interference RNA was used to analyze the involvement of Gal-1/tPA interaction in extracellular signal-regulated kinase 1/2 activation, cell proliferation, and invasion in pancreatic and fibroblastic cells.


RESULTS
Gal-1/tPA interaction is direct, specific, and of high affinity. Gal-1 moderately increases the catalytic activity of tPA. High Gal-1 levels were detected in PDA cells in culture, where it concentrates at the migration front, and in tissues, where it is expressed in epithelial cells and in the stroma. Down-regulation of Gal-1 abolished the effects of tPA on extracellular signal-regulated kinase 1/2 activation, cell proliferation, and invasion, both in pancreatic and in tumor-derived fibroblasts.


CONCLUSIONS
These findings support a new molecular mechanism by which Gal-1 interaction with tPA contributes to PDA progression involving both transformed epithelial cells and tumor fibroblasts.
Roda
Oriol
O
Cancer Research Programme, Municipal Institute of Medical Research, Barcelona, Spain.
Ortiz-Zapater
Elena
E
Martínez-Bosch
Neus
N
Gutiérrez-Gallego
Ricardo
R
Vila-Perelló
Miquel
M
Ampurdanés
Coral
C
Gabius
Hans-Joachim
HJ
André
Sabine
S
Andreu
David
D
Real
Francisco X
FX
Navarro
Pilar
P
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D004195:Disease Models, Animal; D018450:Disease Progression; D015536:Down-Regulation / Q000187:drug effects; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D037483:Galectin 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering / Q000494:pharmacology; D010959:Tissue Plasminogen Activator / Q000378:metabolism*
D037483:Galectin 1; D034741:RNA, Small Interfering; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D010959:Tissue Plasminogen Activator