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 J, Brooks Doug A, Selemidis Stavros
Infection and Immunity Program, Biomedicine Discovery Institute, Department of Pharmacology, Monash University, Melbourne, Victoria 3800, Australia.
Department of Physiology, Anatomy and Microbiology, School of Life Sciences, La Trobe University, Melbourne, Victoria 3086, Australia.
Oncotarget. 2018 Oct 23;9(83):35378-35393. doi: 10.18632/oncotarget.26237.
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 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 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.
活性氧（ROS）促进包括血管内皮生长因子A（VEGF-A）在内的生长因子信号传导，具有强大的血管生成和致瘤特性。然而，ROS产生的确切酶来源、ROS产生的亚细胞定位以及影响肿瘤促进过程的细胞靶点，在很大程度上尚不清楚。在此，我们使用mRNA微阵列显示，与非恶性组织相比，人类原发性前列腺癌中ROS生成的NADPH氧化酶的催化亚基NOX2的基因表达增加。此外，NOX4基因表达在人类转移性前列腺癌中显著升高，但在原发性前列腺肿瘤中未升高。使用前列腺癌的同基因原位小鼠模型，NOX2的基因缺失（即NOX2-/-小鼠）导致血管生成减少，肿瘤发展几乎完全失败。此外，对NOX2氧化酶的药理学抑制抑制了小鼠中已形成的前列腺肿瘤。在分离的内皮细胞以及人类正常和前列腺癌细胞中，NOX2与早期内体标志物（包括EEA1、Appl1和Rab5A）以及晚期内体标志物Rab7A不同程度地共定位，这与酸化内体隔室内显著的VEGF-A依赖性ROS产生以及依赖于NOX2氧化酶和过氧化氢的内皮细胞增殖相关。我们得出结论，NOX2氧化酶表达和内体ROS产生对前列腺癌生长很重要，这是正向调节VEGF通路所必需的。该研究为通过更好地理解NOX2氧化酶对VEGF信号传导的影响以及控制肿瘤脉管系统的发育如何限制前列腺肿瘤的发展和转移提供了一个范例。
