Reactive Oxygen Generated by NADPH Oxidase 1 (Nox1) Contributes to Cell Invasion by Regulating Matrix Metalloprotease-9 Production and Cell Migration2

A mediating role of the reactive oxygen species-generating enzyme Nox1 has been suggested for Ras oncogene transformation phenotypes including anchorage-independent cell growth, augmented angiogenesis, and tumorigenesis. However, little is known about whether Nox1 signaling regulates cell invasivene...

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Bibliographic Details
Published in:The Journal of biological chemistry 2010-02, Vol.285 (7), p.4481-4488
Main Authors: Shinohara, Masahiro, Adachi, Yoshifumi, Mitsushita, Junji, Kuwabara, Mitsuhiro, Nagasawa, Atsushi, Harada, Saori, Furuta, Shuichi, Zhang, Yugen, Seheli, Kajla, Miyazaki, Hitoshi, Kamata, Tohru
Format: Article
Language:English
Subjects:
Cell/Migration
Enzymes/Metallo
Enzymes/Oxidase
Enzymes/Proteolytic
NADPH Oxidases
Nox
Oxygen/Reactive
Proteases/Metalloprotease
Signal Transduction/G-proteins
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Summary:A mediating role of the reactive oxygen species-generating enzyme Nox1 has been suggested for Ras oncogene transformation phenotypes including anchorage-independent cell growth, augmented angiogenesis, and tumorigenesis. However, little is known about whether Nox1 signaling regulates cell invasiveness. Here, we report that the cell invasion activity was augmented in K-Ras-transformed normal rat kidney cells and attenuated by transfection of Nox1 small interference RNAs (siRNAs) into the cells. Diphenyleneiodonium (DPI) or Nox1 siRNAs blocked up-regulation of matrix metalloprotease-9 at both protein and mRNA levels in K-Ras-transformed normal rat kidney cells. Furthermore, DPI and Nox1 siRNAs inhibited the activation of IKKα kinase and the degradation of IκBα, suppressing the NFκB-dependent matrix metalloprotease-9 promoter activity. Additionally, epidermal growth factor-stimulated migration of CaCO-2 cells was abolished by DPI and Nox1 siRNAs, indicating the requirement of Nox1 activity for the motogenic effect of epidermal growth factor. This Nox1 action was mediated by down-regulation of the Rho activity through the low molecular weight protein-tyrosine phosphatase-p190RhoGAP-dependent mechanism. Taken together, our findings define a mediating role of Nox1-generated reactive oxygen species in cell invasion processes, most notably metalloprotease production and cell motile activity.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M109.071779