In light of evidence that inflammation influences the pathogenesis of PCa, these results suggest that inflammatory chemokines, such as CCL5, expressed by prostate cells may act directly on the growth and survival of PCa cells. Chemokine receptor antagonists may thus block autocrine mechanisms of PCa progression.

KIAA1199 serves as a novel cell migration-promoting gene and plays a critical role in maintaining cancer mesenchymal status.

Oxidative stress caused by high levels of reactive oxygen species (ROS) has been correlated with prostate cancer (PCa) aggressiveness. Expression of membrane-type 1-matrix metalloproteinase (MT1-MMP), which has been implicated in cancer invasion and metastasis, is associated with advanced PCa. We demonstrate here that MT1-MMP plays a key role in eliciting oxidative stress in PCa cancer cells. Stable MT1-MMP expression in less invasive LNCaP prostate cancer cells with low endogenous MT1-MMP increased activity of ROS, whereas MT1-MMP knockdown in DU145 cells with high endogenous MT1-MMP decreased ROS. Expression of MT1-MMP increased oxidative DNA damage in LNCaP and in DU145 cells, indicating MT1-MMP-mediated induction of ROS caused oxidative stress. MT1-MMP expression promoted a more aggressive phenotype in LNCaP cells that was dependent on elaboration of ROS. Blocking ROS activity using the ROS scavenger, N-acetylcysteine (NAC), abrogated MT1-MMP-mediated increase in cell migration and invasion. MT1-MMP-expressing LNCaP cells displayed an enhanced ability to grow in soft agar that required increased ROS. Employing cells expressing MT1-MMP mutant cDNAs, we demonstrated that ROS activation entails cell surface MT1-MMP proteolytic activity. Induction of ROS in PCa cells expressing MT1-MMP required adhesion to extracellular matrix (ECM) proteins and was impeded by anti-β1 integrin antibodies. These results highlight a novel mechanism of malignant progression in PCa cells that involves β1 integrin-mediated adhesion, in concert with MT1-MMP proteolytic activity, to elicit oxidative stress and induction of a more invasive phenotype.