EGF promotes invasion by PANC-1 cells through Rac1/ROS-dependent secretion and activation of MMP-2.
Cancer metastasis involves tumor cells invading the surrounding tissue. Remodeling of tissue barriers depends on the ability of tumor cells to degrade the surrounding collagen matrix and then migrate through the matrix defects. Epidermal growth factor (EGF) has been shown to regulate tumor cell invasion through activation of matrix metalloproteinase-2 (MMP-2) in various tumor cell types. In the present study, we investigated the role of MMP-2 and the signaling pathway involved in EGF-promoted invasion by human pancreatic cancer cells PANC-1. Using specific inhibitors, we found that EGF stimulation of these tumor cells induced secretion and activation of the collagenase MMP-2, which was required for EGF-stimulated basement membrane degradation and cell invasion. Our results also indicate that signaling events downstream of EGF receptor involved PI3K- and Src-dependent activation of Rac1, which mediated the NADPH-generated reactive oxygen species responsible for MMP-2 secretion and activation.
Binker
Marcelo G
MG
CBRHC Research Center, Biosciences, Arribenos 1697, P.1, Buenos Aires 1426, Argentina.
Binker-Cosen
Andres A
AA
Richards
Daniel
D
Oliver
Brenda
B
Cosen-Binker
Laura I
LI
D045744:Cell Line, Tumor; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D009249:NADP / Q000378:metabolism; D009361:Neoplasm Invasiveness; 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*; D019061:src-Family Kinases / Q000378:metabolism
D061965:Matrix Metalloproteinase Inhibitors; D017382:Reactive Oxygen Species; D009249:NADP; D004815:Epidermal Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D019061:src-Family Kinases; D020778:Matrix Metalloproteinase 2; D020830:rac1 GTP-Binding Protein