NOX2 oxidase expressed in endosomes promotes cell proliferation and prostate tumour development

Harrison, I, Vinh, A, Johnson, I, Luong, R, Drummond, G, Sobey, C, Tiganis, T, Williams, E, O'Leary, J, Brooks, D and Selemidis, S 2018, 'NOX2 oxidase expressed in endosomes promotes cell proliferation and prostate tumour development', OncoTarget, vol. 9, no. 83, pp. 35378-35393.


Document type: Journal Article
Collection: Journal Articles

Title NOX2 oxidase expressed in endosomes promotes cell proliferation and prostate tumour development
Author(s) Harrison, I
Vinh, A
Johnson, I
Luong, R
Drummond, G
Sobey, C
Tiganis, T
Williams, E
O'Leary, J
Brooks, D
Selemidis, S
Year 2018
Journal name OncoTarget
Volume number 9
Issue number 83
Start page 35378
End page 35393
Total pages 16
Publisher Impact Journals LLC
Abstract Reactive oxygen species (ROS) promote growth factor signalling including for VEGF-A and have potent angiogenic and tumourigenic properties. However, the precise enzymatic source of ROS generation, the subcellular localization of ROS production and cellular targets in vivo that influence tumour-promoting processes, are largely undefined. Here, using mRNA microarrays, we show increased gene expression for NOX2, the catalytic subunit of the ROS-generating NADPH oxidase enzyme, in human primary prostate cancer compared to non-malignant tissue. In addition, NOX4 gene expression was markedly elevated in human metastatic prostate cancers, but not in primary prostate tumours. Using a syngeneic, orthotopic mouse model of prostate cancer the genetic deletion of NOX2 (i.e. NOX2-/y mouse) resulted in reduced angiogenesis and an almost complete failure in tumour development. Furthermore, pharmacological inhibition of NOX2 oxidase suppressed established prostate tumours in mice. In isolated endothelial cells, and in human normal and prostate cancer cells, NOX2 co-located to varying degrees with early endosome markers including EEA1, Appl1 and Rab5A and the late endosome marker Rab7A, and this correlated with significant VEGF-A-dependent ROS production within acidified endosomal compartments and endothelial cell proliferation that was NOX2 oxidase- and hydrogen peroxide dependent. We concluded that NOX2 oxidase expression and endosomal ROS production were important for prostate cancer growth and that this was required to positively regulate the VEGF pathway. The research provides a paradigm for limiting tumour growth through a better understanding of NOX2 oxidase's effect on VEGF signalling and how controlling the development of tumour vasculature can limit prostate tumour development and metastasis.
Subject Cancer Cell Biology
Keyword(s) NOX2
NADPH oxidase
endosome
reactive oxygen species
prostate cancer
DOI - identifier 10.18632/oncotarget.26237
Copyright notice © Copyright: Harrison et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0),
ISSN 1949-2553
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