Journal
BIOCHEMICAL PHARMACOLOGY
Volume 86, Issue 2, Pages 253-266Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2013.05.011
Keywords
NOX4; Metastasis; TGF-beta; Reactive oxygen species (ROS); Schisandrin B
Categories
Funding
- China National 973 project [2013CB911303]
- China Natural Sciences Foundation projects [81071802, 81272456]
- Fundamental Research Funds for the Central Universities, National Ministry of Education, China
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Cancer metastasis is a major cause for cancer-related death and inhibiting cancer metastasis is an alternative way to treat cancer. Several lines of reported evidence suggest that NADPH oxidase 4 (NOX4) is a potential target for intervention of cancer metastasis, as the reactive oxygen species (ROS) generated by this enzyme plays important roles in TGF-beta signaling, an important inducer of cancer metastasis. Here we show (1) that TGF-beta induces ROS production in breast cancer 4T1 cells and enhances cell migration and that the effect of TGF-beta depends on NOX4 expression, (2) that knockdown of NOX4 via RNAi significantly decreases the migration ability of 4T1 cells in the presence or absence of TGF-beta and significantly attenuates distant metastasis of 4T1 cells to lung and bone, (3) that Schisandrin B (Sch B), a naturally occurring dibenzocyclooctadiene lignan with very low toxicity, is a novel NOX inhibitor and its IC50 toward NOX4 is 9.3 mu M, and (4) that Sch B suppresses TGF-beta-induced and NOX4-associated ROS production in 4T1 cells and inhibits TGF-beta-enhanced cell migration. Similar to NOX4 knockdown observed in this study, Sch B significantly attenuated 411 cells distant metastasis to lung and bone in our recently published study. In line with previous reports, the study suggests that pharmacologically targeting NOX4 may be a potential approach to disrupt cancer metastasis. (C) 2013 Elsevier Inc. All rights reserved.
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