title: Oxidative stress and prostate cancer progression are elicited by membrane-type 1 matrix metalloproteinase.
abstract: Oxidative stress caused by high levels of reactive oxygen species (ROS) has been correlated with prostate cancer aggressiveness. Expression of membrane-type 1 matrix metalloproteinase (MT1-MMP), which has been implicated in cancer invasion and metastasis, is associated with advanced prostate cancer. We show here that MT1-MMP plays a key role in eliciting oxidative stress in prostate 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 activity of ROS. Expression of MT1-MMP increased oxidative DNA damage in LNCaP and in DU145 cells, indicating that 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 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. Using cells expressing MT1-MMP mutant cDNAs, we showed that ROS activation entails cell surface MT1-MMP proteolytic activity. Induction of ROS in prostate cancer cells expressing MT1-MMP required adhesion to extracellular matrix proteins and was impeded by anti-β1 integrin antibodies. These results highlight a novel mechanism of malignant progression in prostate cancer 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.
authors.affiliation: Division of Cancer Prevention, Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Hoang-Lan
authors.initials: HL
authors.lastname: Nguyen
authors.forename: Stanley
authors.initials: S
authors.lastname: Zucker
authors.forename: Kevin
authors.initials: K
authors.lastname: Zarrabi
authors.forename: Pournima
authors.initials: P
authors.lastname: Kadam
authors.forename: Cathleen
authors.initials: C
authors.lastname: Schmidt
authors.forename: Jian
authors.initials: J
authors.lastname: Cao
mesh_terms: D000818:Animals; D018450:Disease Progression; D006801:Humans; D008297:Male; D053511:Matrix Metalloproteinase 14 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018384:Oxidative Stress / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D014162:Transfection
chemical_list: D017382:Reactive Oxygen Species; D053511:Matrix Metalloproteinase 14