NOX2 oxidase expressed in endosomes promotes cell proliferation and prostate tumour development
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Ian P. Harrison1, Antony Vinh2, Ian R.D. Johnson3, Raymond Luong1, Grant R. Drummond2, Christopher G. Sobey2, Tony Tiganis4, Elizabeth D. Williams5, John J. O’ Leary6,7, Doug A. Brooks3 and Stavros Selemidis1,8
1Infection and Immunity Program, Biomedicine Discovery Institute, Department of Pharmacology, Monash University, Melbourne, Victoria 3800, Australia
2Department of Physiology, Anatomy and Microbiology, School of Life Sciences, La Trobe University, Melbourne, Victoria 3086, Australia
3School of Pharmacy and Medical Sciences, University of South Australia Cancer Research Institute, University of South Australia, Adelaide, South Australia 5001, Australia
4Metabolic Disease and Obesity Program, Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Victoria 3800, Australia
5Australian Prostate Cancer Research Centre-Queensland, School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Resea rch Institute, Brisbane, Queensland 4000, Australia
6Histopathology, School of Medicine Trinity College Dublin, Ireland, Sir Patrick Dun’s Laboratory, Central Pathology Laboratory, St James’s Hospital, Dublin 8, Ireland
7Emer Casey Research Laboratory, Molecular Pathology Laboratory, The Coombe Women and Infants University Hospital, Dublin 8, Ireland
8Program in Chronic Infectious and Inflammatory Diseases, School of Health and Biomedical Sciences, College of Science, Engineering and Health, RMIT University, Bundoora, Victoria 3083, Australia
Stavros Selemidis, email: Stavros.selemidis@RMIT.edu.au
Keywords: NOX2; NADPH oxidase; endosome; reactive oxygen species; prostate cancer
Received: July 31, 2018 Accepted: October 06, 2018 Published: October 23, 2018
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.
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