title: DUOX enzyme activity promotes AKT signalling in prostate cancer cells.
abstract: Reactive oxygen species (ROS) and oxidative stress are related to tumour progression, and high levels of ROS have been observed in prostate tumours compared to normal prostate. ROS can positively influence AKT signalling and thereby promote cell survival. The aim of this project was to establish whether the ROS generated in prostate cancer cells positively regulate AKT signalling and enable resistance to apoptotic stimuli. In PC3 cells, dual oxidase (DUOX) enzymes actively generate ROS, which inactivate phosphatases, thereby maintaining AKT phosphorylation. Inhibition of DUOX by diphenylene iodium (DPI), intracellular calcium chelation and small-interfering RNA (siRNA) resulted in lower ROS levels, lower AKT and glycogen synthase kinase 3β (GSK3β) phosphorylation, as well as reduced cell viability and increased susceptibility to apoptosis stimulating fragment (FAS) induced apoptosis. This report shows that ROS levels in PC3 cells are constitutively maintained by DUOX enzymes, and these ROS positively regulate AKT signalling through inactivating phosphatases, leading to increased resistance to apoptosis.
authors.affiliation: Tumour Biology Laboratory, BioSciences Institute, University College Cork, College Road, Cork, Ireland.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Pettigrew
authors.forename: John S
authors.initials: JS
authors.lastname: Clerkin
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Cotter
mesh_terms: D045744:Cell Line, Tumor; D000074623:Dual Oxidases; D004789:Enzyme Activation; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000074664:NADPH Oxidase 5; D019255:NADPH Oxidases / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection
chemical_list: D008565:Membrane Proteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D000074623:Dual Oxidases; D000074664:NADPH Oxidase 5; D019255:NADPH Oxidases; C431571:NOX5 protein, human; C086986:CYBA protein, human; C431513:DUOX1 protein, human; C431515:DUOX2 protein, human; D051058:Oncogene Protein v-akt