Carcinogenesis and Reactive Oxygen Species Signaling: Interaction of the NADPH Oxidase NOX1–5 and Superoxide Dismutase 1–3 Signal Transduction Pathways

Parascandolo, Alessia; Laukkanen, Mikko O.

doi:10.1089/ars.2017.7268

Cited by 81 publications

(67 citation statements)

References 398 publications

(548 reference statements)

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“…Reactive oxygen species (ROS) are a by‐product of mitochondrial oxidative phosphorylation that seem to also act as signaling molecules for both cell proliferation and cell death 7 . The alteration of ROS levels has thus been associated with various processes involved in the occurrence and development of cancer, including aging, 8 carcinogenesis, 9 tumor progression, 10 metastasis, 11 and tumor survival 12 …”

Section: Introductionmentioning

confidence: 99%

“…The alteration of ROS levels has thus been associated with various processes involved in the occurrence and development of cancer, including aging, 8 carcinogenesis, 9 tumor progression, 10 metastasis, 11 and tumor survival. 12 Under normal physiological conditions, the cells have a comprehensive antioxidant defense system for eliminating excessive ROS and regulating redox status.…”

Section: Introductionmentioning

confidence: 99%

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Redox regulation by SOD2 modulates colorectal cancer tumorigenesis through AMPK‐mediated energy metabolism

Zhou

Lyu

Miao

et al. 2020

Molecular Carcinogenesis

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Colorectal cancer (CRC) is a common malignancy. Many reports have implicated aberrant mitochondrial activity in the progression of CRC, with particular emphasis on the dysregulation of redox signaling and oxidative stress. In this study, we focused on manganese superoxide dismutase (MnSOD/SOD2), a key antioxidant enzyme, which maintains intracellular redox homeostasis. Current literature presents conflicting mechanisms for how SOD2 influences tumorigenesis and tumor progression. Here, we explored the role of SOD2 in CRC specifically. We found high levels of SOD2 expression in CRC tissues. We carried out a series of experiments to determine whether knockdown of SOD2 expression in CRC cell lines would reverse features of tumorigenesis. We found that reduced SOD2 expression decreased cell proliferation, migration, and invasion activity in CRC cells. Results from an additional series of experiments on mitochondrial function implicated a dual role for SOD2 in promoting CRC progression. First, proper level of SOD2 helped CRC cells maintain mitochondrial function by disposal of superoxide (O2.−). Second, over‐expression of SOD2 induced H2O2‐mediated tumorigenesis by upregulating AMPK and glycolysis. Our results indicate that SOD2 may promote the occurrence and development of CRC by regulating the energy metabolism mediated by AMPK signaling pathways.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Redox regulation by SOD2 modulates colorectal cancer tumorigenesis through AMPK‐mediated energy metabolism

Zhou

Lyu

Miao

et al. 2020

Molecular Carcinogenesis

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“…Nox1, the first Nox2 homologue to be discovered, requires cytosolic subunits p47phox (or the homologues NOXO1 and NOXO1 ) and p67phox (NOXA1) for its activation (Suh et al, 1999;Takeya et al, 2003). It is most abundant in colon, prostate, uterus and vascular cells, and its expression is markedly increased in cancer cells (Juhasz et al, 2017;Parascandolo & Laukkanen, 2019). Nox1 was originally called Mox1 for 'mitogenic oxidase' because of its role in cell proliferation and mitogenesis (Suh et al, 1999).…”

Section: A Primer On Nox Isoformsmentioning

confidence: 99%

NOX5: Molecular biology and pathophysiology

Touyz

Anagnostopoulou

Ríos

et al. 2019

Experimental Physiology

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New Findings What is the topic of this review? This review provides a comprehensive overview of Nox5 from basic biology to human disease and highlights unique features of this Nox isoform What advances does it highlight? Major advances in Nox5 biology relate to crystallization of the molecule and new insights into the pathophysiological role of Nox5. Recent discoveries have unravelled the crystal structure of Nox5, the first Nox isoform to be crystalized. This provides new opportunities to develop drugs or small molecules targeted to Nox5 in an isoform‐specific manner, possibly for therapeutic use. Moreover genome wide association studies (GWAS) identified Nox5 as a new blood pressure‐associated gene and studies in mice expressing human Nox5 in a cell‐specific manner have provided new information about the (patho) physiological role of Nox5 in the cardiovascular system and kidneys. Nox5 seems to be important in the regulation of vascular contraction and kidney function. In cardiovascular disease and diabetic nephropathy, Nox5 activity is increased and this is associated with increased production of reactive oxygen species and oxidative stress implicated in tissue damage. Abstract Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Nox), comprise seven family members (Nox1–Nox5 and dual oxidase 1 and 2) and are major producers of reactive oxygen species in mammalian cells. Reactive oxygen species are crucially involved in cell signalling and function. All Noxs share structural homology comprising six transmembrane domains with two haem‐binding regions and an NADPH‐binding region on the intracellular C‐terminus, whereas their regulatory systems, mechanisms of activation and tissue distribution differ. This explains the diverse function of Noxs. Of the Noxs, NOX5 is unique in that rodents lack the gene, it is regulated by Ca 2+ , it does not require NADPH oxidase subunits for its activation, and it is not glycosylated. NOX5 localizes in the perinuclear and endoplasmic reticulum regions of cells and traffics to the cell membrane upon activation. It is tightly regulated through numerous post‐translational modifications and is activated by vasoactive agents, growth factors and pro‐inflammatory cytokines. The exact pathophysiological significance of NOX5 remains unclear, but it seems to be important in the physiological regulation of sperm motility, vascular contraction and lymphocyte differentiation, and NOX5 hyperactivation has been implicated in cardiovascular disease, kidney injury and cancer. The field of NOX5 biology is still in its infancy, but with new insights into its biochemistry and cellular regulation, discovery of the NOX5 crystal structure and genome‐wide association studies implicating NOX5 in disease, the time is now ripe to advance NOX5 research. This review provides a comprehensive overview of our current understanding of NOX5, from basic ...

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“…GPX3 plays an important role in suppressing prostate cancer by removing ROS. We identified how Gpx3 knockout affected the mRNA expression of oxidative stress‐related genes in the prostate Figure 2A Sod3 acts as an antioxidant by metabolizing extracellular superoxide to H 2 O 2 31 . Reduction of the expression of the antioxidant enzyme Gpx2 was reported in Nkx3.1 KO mice 13 .…”

Section: Resultsmentioning

confidence: 98%

Loss of glutathione peroxidase 3 induces ROS and contributes to prostatic hyperplasia in Nkx3.1 knockout mice

Kim

Lee

et al. 2020

Andrology

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Background Glutathione peroxidase 3 (Gpx3) protects cells from oxidative stress, and its reduced expression in human prostate cancer has been reported. Objectives We hypothesized that Gpx3 might play an important role in the development of prostatic intraepithelial neoplasia (PIN), a pre‐cancerous state of the prostate, and aimed to highlight the underlying molecular mechanism. Materials and Methods The following double‐knockout mice Nkx3.1−/−; Gpx3+/+, Nkx3.1−/−; Gpx3+/−, Nkx3.1−/−; Gpx3−/− were produced. Randomly divided animals were weighed, and their genitourinary tract (GUT) weights were determined after euthanasia at 4, 8, and 12 months. The mRNA expression of the genes involved in oxidative stress and Wnt signaling was analyzed in the prostate. Histopathology, ROS, and superoxide dismutase (SOD) activities were also measured. Results Loss of Gpx3 did not affect body weight and GUT weight in Nkx3.1 knockout mice. The mRNA expression of SOD3, iNOS, Hmox, and CISD2, which are associated with oxidative stress, was increased in Nkx3.1−/−; Gpx3−/− mice at 4 months but decreased at 8 and 12 months. There was no change in β‐catenin and its targets associated with Wnt signaling. Increased ROS and decreased SOD activity were observed in Nkx3.1−/−; Gpx3−/− mice at 12 months of age. The histopathologic score and epithelium thickness were increased, and lumen area was decreased in Gpx3 knockout mice. Discussion and Conclusions Gpx3 loss increased the hyperplasia of PIN in the pre‐cancerous stage of the prostate. Loss of Gpx3 induced oxidative stress. Histopathologically, no invasive carcinoma was identified, and Gpx3 loss did not increase Wnt/β‐catenin signaling. Further research on the role of GPX3 in the transition of PIN to invasive carcinoma is needed. We show, for the first time, that the antioxidant enzyme GPX3 plays a vital role in inhibiting hyperplasia in the PIN stage of the prostate gland in vivo.

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Carcinogenesis and Reactive Oxygen Species Signaling: Interaction of the NADPH Oxidase NOX1–5 and Superoxide Dismutase 1–3 Signal Transduction Pathways

Abstract: The clarification of interaction of signal transduction pathways could explain how cells regulate redox balance and may even provide means to inhibit the accumulation of harmful levels of ROS in human pathologies. Antioxid. Redox Signal. 00, 000-000.

Cited by 81 publications

References 398 publications

Redox regulation by SOD2 modulates colorectal cancer tumorigenesis through AMPK‐mediated energy metabolism

Redox regulation by SOD2 modulates colorectal cancer tumorigenesis through AMPK‐mediated energy metabolism

NOX5: Molecular biology and pathophysiology

Loss of glutathione peroxidase 3 induces ROS and contributes to prostatic hyperplasia in Nkx3.1 knockout mice

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