Hypoxia-reoxygenation increase invasiveness of PANC-1 cells through Rac1/MMP-2.
Pancreatic cancer is an aggressive malignancy with proclivity to early metastasis. High expression and activation of the collagenase matrix metalloproteinase-2 (MMP-2) have been found in human pancreatic cancer tissues, being these increased levels of active MMP-2 correlated to tumor invasion and metastasis. Hypoxia and reoxygenation (H-R) are critical pathophysiological conditions during ischemia-reperfusion injury, which has been shown to enhance both invasion and metastasis. In the present study, we investigated the effects of H-R on MMP-2 levels and the invasiveness properties of human pancreatic cancer cells PANC-1. Using specific inhibitors, we found that H-R treatment of these tumor cells induced secretion and activation of MMP-2, which was required for H-R-stimulated basement membrane degradation and cell invasion. Our results also indicate that signaling events involved in H-R-enhanced PANC-1 invasiveness comprehend PI3K-dependent activation of Rac1, which mediated the formation of NADPH-generated reactive oxygen species responsible for MMP-2 secretion and activation.
Department of Medicine and Physiology, University of Toronto, Toronto, Ontario, Canada.
Marcelo G
MG
Binker
Andres A
AA
Binker-Cosen
Daniel
D
Richards
Herbert Y
HY
Gaisano
Rodica H
RH
de Cosen
Laura I
LI
Cosen-Binker
D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010100:Oxygen / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
C107953:RAC1 protein, human; D017382:Reactive Oxygen Species; D009249:NADP; D019869:Phosphatidylinositol 3-Kinases; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D020830:rac1 GTP-Binding Protein; D010100:Oxygen