期刊
MOLECULAR CANCER RESEARCH
卷 9, 期 10, 页码 1305-1318出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-11-0033
关键词
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资金
- NIH [5RO1CA11355301A1, RO1CA11355301S1]
- Walk-for-Beauty Foundation
- Walk for Beauty Foundation
- Carol Baldwin Breast Cancer Foundation
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-beta 1 integrin antibodies. These results highlight a novel mechanism of malignant progression in prostate cancer cells that involves beta 1 integrin-mediated adhesion, in concert with MT1-MMP proteolytic activity, to elicit oxidative stress and induction of a more invasive phenotype. Mol Cancer Res; 9(10); 1305-18. (C) 2011 AACR.
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