title: Inhibiting cancer metastasis via targeting NAPDH oxidase 4.
abstract: 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-β signaling, an important inducer of cancer metastasis. Here we show (1) that TGF-β induces ROS production in breast cancer 4T1 cells and enhances cell migration and that the effect of TGF-β 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-β 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 9.3μM, and (4) that Sch B suppresses TGF-β-induced and NOX4-associated ROS production in 4T1 cells and inhibits TGF-β-enhanced cell migration. Similar to NOX4 knockdown observed in this study, Sch B significantly attenuated 4T1 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.
authors.affiliation: Cancer Institute a Key Laboratory for Cancer Prevention & Intervention, National Ministry of Education, China.
authors.forename: Biao
authors.initials: B
authors.lastname: Zhang
authors.forename: Zhen
authors.initials: Z
authors.lastname: Liu
authors.forename: Xun
authors.initials: X
authors.lastname: Hu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D034242:Cyclooctanes / Q000494:pharmacology; D005260:Female; D006801:Humans; D017705:Lignans / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D018613:Microscopy, Confocal; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009362:Neoplasm Metastasis; D011083:Polycyclic Compounds / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000502:physiology
chemical_list: D034242:Cyclooctanes; D017705:Lignans; D011083:Polycyclic Compounds; D017382:Reactive Oxygen Species; D016212:Transforming Growth Factor beta; C015499:schizandrin B; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse