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1 Department of Medicine, Veterans Affairs Greater Los Angeles Healthcare System and University of California, Los Angeles, CA, USA
2 Department of Medicine, Veterans Affairs Greater Los Angeles Healthcare System and University of California, Los Angeles, CA, USA; Department of General Surgery, University of Heidelberg, Heidelberg, Germany
3 Department of General Surgery, University of Heidelberg, Heidelberg, Germany
4 Department of Gastroenterology, Endocrinology and Nutrition, Ernst-Moritz-Arndt Universitat, Greifswald, Germany
* To whom correspondence should be addressed. E-mail: agukovsk{at}ucla.edu.
Extracellular matrix (ECM) facilitates pancreatic cancer cells survival, which is of central importance for pancreatic adenocarcinoma that is highly fibrotic. Here we show that reactive oxygen species (ROS) mediate the prosurvival effect of ECM in human pancreatic cancer cells. Fibronectin and laminin stimulated ROS production and NADPH oxidase activation in pancreatic cancer cells. Both pharmacologic and molecular approaches show that fibronectin stimulated ROS production through activation of NADPH oxidase and NADPH oxidase-independent pathways, and that 5-lipoxygenase (5-LO) mediates both these pathways. Analysis of the mechanisms of ROS production by ECM proteins and growth factors indicate that activation of NADPH oxidase, Nox4 is a common mechanism employed by both ECM proteins and growth factors to increase ROS in pancreatic cancer cells. We also found that Nox4 is present in human pancreatic adenocarcinoma tissues, and that these tissues display membrane NADPH oxidase activity. ECM proteins and growth factors activate NADPH oxidase through different mechanisms; by contrast to ECM proteins, growth factors activate NADPH oxidase through 5- LO-independent mechanisms. Inhibiting 5-LO or NADPH oxidase with pharmacologic inhibitors of these enzymes and with Nox4 or 5-LO antisense oligonucleotides markedly stimulated apoptosis in cancer cells cultured on fibronectin. Our results indicate that ROS generation via 5- LO and downstream NADPH oxidase mediates the prosurvival effect of ECM in pancreatic cancer cells. These mechanisms may play an important role in pancreatic cancer resistance to treatments and thus represent novel therapeutic targets.
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