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

Ian P. Harrison, Antony Vinh, Ian R D Johnson, Raymond Luong, Grant R. Drummond, Christopher G. Sobey, Tony Tiganis, Elizabeth D. Williams, John O'Leary, Doug A. Brooks, Stavros Selemidis

Research output: Contribution to journalArticleResearchpeer-review

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 limitingtumour 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.

Original languageEnglish
Pages (from-to)35378-35393
Number of pages16
JournalOncotarget
Volume9
Issue number83
DOIs
Publication statusPublished - 23 Oct 2018

Keywords

  • Endosome
  • NADPH oxidase
  • NOX2
  • Prostate cancer
  • Reactive oxygen species

Cite this

Harrison, Ian P. ; Vinh, Antony ; Johnson, Ian R D ; Luong, Raymond ; Drummond, Grant R. ; Sobey, Christopher G. ; Tiganis, Tony ; Williams, Elizabeth D. ; O'Leary, John ; Brooks, Doug A. ; Selemidis, Stavros. / NOX2 oxidase expressed in endosomes promotes cell proliferation and prostate tumour development. In: Oncotarget. 2018 ; Vol. 9, No. 83. pp. 35378-35393.
@article{6cf3d6c603f74a139cbe1b0e26080277,
title = "NOX2 oxidase expressed in endosomes promotes cell proliferation and prostate tumour development",
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 limitingtumour 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.",
keywords = "Endosome, NADPH oxidase, NOX2, Prostate cancer, Reactive oxygen species",
author = "Harrison, {Ian P.} and Antony Vinh and Johnson, {Ian R D} and Raymond Luong and Drummond, {Grant R.} and Sobey, {Christopher G.} and Tony Tiganis and Williams, {Elizabeth D.} and John O'Leary and Brooks, {Doug A.} and Stavros Selemidis",
year = "2018",
month = "10",
day = "23",
doi = "10.18632/oncotarget.26237",
language = "English",
volume = "9",
pages = "35378--35393",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "83",

}

NOX2 oxidase expressed in endosomes promotes cell proliferation and prostate tumour development. / Harrison, Ian P.; Vinh, Antony; Johnson, Ian R D; Luong, Raymond; Drummond, Grant R.; Sobey, Christopher G.; Tiganis, Tony; Williams, Elizabeth D.; O'Leary, John; Brooks, Doug A.; Selemidis, Stavros.

In: Oncotarget, Vol. 9, No. 83, 23.10.2018, p. 35378-35393.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - NOX2 oxidase expressed in endosomes promotes cell proliferation and prostate tumour development

AU - Harrison, Ian P.

AU - Vinh, Antony

AU - Johnson, Ian R D

AU - Luong, Raymond

AU - Drummond, Grant R.

AU - Sobey, Christopher G.

AU - Tiganis, Tony

AU - Williams, Elizabeth D.

AU - O'Leary, John

AU - Brooks, Doug A.

AU - Selemidis, Stavros

PY - 2018/10/23

Y1 - 2018/10/23

N2 - 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 limitingtumour 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.

AB - 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 limitingtumour 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.

KW - Endosome

KW - NADPH oxidase

KW - NOX2

KW - Prostate cancer

KW - Reactive oxygen species

UR - http://www.scopus.com/inward/record.url?scp=85055664241&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.26237

DO - 10.18632/oncotarget.26237

M3 - Article

VL - 9

SP - 35378

EP - 35393

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 83

ER -