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.