Inhibition of NADPH oxidase 4 induces apoptosis in malignant mesothelioma: Role of reactive oxygen species

Tanaka, Motoya; Miura, Yuji; Numanami, Hiroki; Karnan, Sivasundaram; Ota, Akinobu; Konishi, Hiroyuki; Hosokawa, Yoshitaka; Hanyuda, Masayuki

doi:10.3892/or.2015.4155

Cited by 16 publications

(9 citation statements)

References 36 publications

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“…Nox/Duox family members are regarded as major sources of ROS generation, which plays an important role in cancer development (9,16). It has been reported that inhibition of Nox activity induces apoptosis in a number of cancerous cells including pancreatic cancer, mesothelioma and sarcoma (17)(18)(19). In the present study, we demonstrated that knockdown of Nox1 but not Nox4 significantly reduced the cell viability in a subset of OSCC cell lines.…”

Section: Discussionsupporting

confidence: 58%

Inhibition of Nox1 induces apoptosis by attenuating the AKT signaling pathway in oral squamous cell carcinoma cell lines

et al. 2016

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NADPH oxidases, also known as the Nox family, are major sources of reactive oxygen species generation that regulate redox-sensitive signaling pathways. Recent studies have implicated the Nox family in cancer development and progression. However, the involvement of its members in the development of oral squamous cell carcinoma (OSCC) remains to be elucidated. To clarify this issue, we first analyzed mRNA expression of Nox/Duox family members (Nox1, Nox2, Nox3, Nox4, Nox5, Duox1 and Duox2) in five OSCC cell lines. Nox1 and Nox4 mRNAs were highly expressed in four OSCC cell lines. Western blot analysis revealed that the protein expression level of Nox1 was higher than that of Nox4 in the OSCC cell lines. In addition, knockdown of Nox1, but not Nox4, significantly suppressed cell viability and induced apoptosis in the HSC-2 and HSC-3 cells. We also found that a specific AKT inhibitor, perifosine, dose-dependently suppressed OSCC cell growth. Notably, Nox1 knockdown significantly attenuated the phosphorylation level of AKT. Furthermore, both Nox1 knockdown and perifosine treatment markedly enhanced the cisplatin-induced cytotoxic effect. Taken together, our results highlight that the Nox1/AKT signaling pathway plays an important role in cell survival in OSCC cells.

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Section: Discussionsupporting

confidence: 58%

Inhibition of Nox1 induces apoptosis by attenuating the AKT signaling pathway in oral squamous cell carcinoma cell lines

et al. 2016

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“…Mitochondrial-localized NADPH-oxidase 4 (Nox4) also produces mROS predominantly in the form H 2 O 2 15,16 . Nox4 is implicated in the pathophysiology of numerous disease processes and its inhibition can induce mesothelioma cell apoptosis 9,17 ; however the signaling events that drive the latter process are yet undefined. In addition, monoaminoxidase (MAO), an important flavoprotein resident of the outer mitochondrial membrane, is another H 2 O 2 generator during ischemia/reperfusion injury in the brain and heart 18–20 .…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial ROS control of cancer

Idelchik

Begley

et al. 2017

Seminars in Cancer Biology

252

169

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Mitochondria serve a primary role in energy maintenance but also function to govern levels of mitochondria-derived reactive oxygen species (mROS). ROS have long been established to play a critical role in tumorigenesis and are now considered to be integral to the regulation of diverse signaling networks that drive proliferation, tumor cell survival and malignant progression. mROS can damage DNA, activate oncogenes, block the function of tumor suppressors and drive migratory signaling. The mitochondrion's oxidant scavenging systems including SOD2, Grx2, GPrx, Trx and TrxR are key of the cellular redox tone. These mitochondrial antioxidant systems serve to tightly control the levels of the primary ROS signaling species, H2O2. The coordinated control of mROS levels is also coupled to the activity of the primary H2O2 consuming enzymes of the mitochondria which are reliant on the epitranscriptomic control of selenocysteine incorporation. This review highlights the interplay between these many oncogenic signaling networks, mROS and the H2O2 emitting and consuming capacity of the mitochondria.

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“…Taken together, our results indicate a role for NOX-generated ROS in hypoxia-independent HIF1␣ stabilization. Preliminary findings and other studies suggest that NOX4, one of the five human NOX homologues, is of particular interest within our paradigm (58)(59)(60)(61)(62)(63)(64)(65).…”

Section: Discussionmentioning

confidence: 65%

Reactive Oxygen Species Signaling Promotes Hypoxia-Inducible Factor 1α Stabilization in Sonic Hedgehog-Driven Cerebellar Progenitor Cell Proliferation

Eyrich

Potts

Robinson

et al. 2019

Molecular and Cellular Biology

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Cerebellar development is a highly regulated process involving numerous factors acting with high specificity, both temporally and by location. Part of this process involves extensive proliferation of cerebellar granule neuron precursors (CGNPs) induced by Sonic Hedgehog (SHH) signaling, but downstream effectors of mitogenic signaling are still being elucidated. Using primary CGNP cultures, a well-established model for SHH-driven proliferation, we show that SHH-treated CGNPs feature high levels of hypoxia-inducible factor 1α (HIF1α), which is known to promote glycolysis, stemness, and angiogenesis. In CGNPs cultured under normoxic conditions, HIF1α is posttranslationally stabilized in a manner dependent upon reactive oxygen species (ROS) and NADPH oxidase (NOX), both of which are also upregulated in these cells. Inhibition of NOX activity resulted in HIF1α destabilization and reduced levels of cyclin D2, a marker of CGNP proliferation. As CGNPs are the putative cells of origin for the SHH subtype of medulloblastoma and aberrant SHH signaling is implicated in other neoplasms, these studies may also have future relevance in the context of cancer. Taken together, our findings suggest that a better understanding of nonhypoxic HIF1α stabilization through NOX-induced ROS generation can provide insights into normal cell proliferation in cerebellar development and SHH-driven cell proliferation in cancers with aberrant SHH signaling.

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Inhibition of NADPH oxidase 4 induces apoptosis in malignant mesothelioma: Role of reactive oxygen species

Cited by 16 publications

References 36 publications

Inhibition of Nox1 induces apoptosis by attenuating the AKT signaling pathway in oral squamous cell carcinoma cell lines

Inhibition of Nox1 induces apoptosis by attenuating the AKT signaling pathway in oral squamous cell carcinoma cell lines

Mitochondrial ROS control of cancer

Reactive Oxygen Species Signaling Promotes Hypoxia-Inducible Factor 1α Stabilization in Sonic Hedgehog-Driven Cerebellar Progenitor Cell Proliferation

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