bims-noxint Biomed News
on NADPH oxidases in tumorigenesis
Issue of 2022–03–13
seven papers selected by
Laia Caja Puigsubira, Uppsala University
  1. NADPH Oxidase 4 (NOX4) in Cancer: Linking Redox Signals to Oncogenic Metabolic Adaptation.
  2. Independent of Renox, NOX5 Promotes Renal Inflammation and Fibrosis in Diabetes by Activating ROS-sensitive Pathways.
  3. Inhibition of endothelial Nox2 activation by LMH001 protects mice from angiotensin II-induced vascular oxidative stress, hypertension and aortic aneurysm.
  4. Inhibition of the NADPH Oxidase Pathway Reduces Ferroptosis during Septic Renal Injury in Diabetic Mice.
  5. NADPH Oxidase 3 Deficiency Protects From Noise-Induced Sensorineural Hearing Loss.
  6. Prognostic Value of NOX4 Expression in Cancer Patients: A Systematic Review and Meta-analysis.
  7. Diesel Particulate Extract Accelerates Premature Skin Aging in Human Fibroblasts via Ceramide-1-Phosphate-Mediated Signaling Pathway.
  1. Int J Mol Sci. 2022 Feb 28. pii: 2702. [Epub ahead of print]23(5):
    NADPH Oxidase 4 (NOX4) in Cancer: Linking Redox Signals to Oncogenic Metabolic Adaptation.
    Ildiko Szanto.
      Cancer cells can survive and maintain their high proliferation rate in spite of their hypoxic environment by deploying a variety of adaptative mechanisms, one of them being the reorientation of cellular metabolism. A key aspect of this metabolic rewiring is the promotion of the synthesis of antioxidant molecules in order to counter-balance the hypoxia-related elevation of reactive oxygen species (ROS) production and thus combat the onset of cellular oxidative stress. However, opposite to their negative role in the inception of oxidative stress, ROS are also key modulatory components of physiological cellular metabolism. One of the major physiological cellular ROS sources is the NADPH oxidase enzymes (NOX-es). Indeed, NOX-es produce ROS in a tightly regulated manner and control a variety of cellular processes. By contrast, pathologically elevated and unbridled NOX-derived ROS production is linked to diverse cancerogenic processes. In this respect, NOX4, one of the members of the NOX family enzymes, is of particular interest. In fact, NOX4 is closely linked to hypoxia-related signaling and is a regulator of diverse metabolic processes. Furthermore, NOX4 expression and function are altered in a variety of malignancies. The aim of this review is to provide a synopsis of our current knowledge concerning NOX4-related processes in the oncogenic metabolic adaptation of cancer cells.
    Keywords:  NADPH oxidase; cancer; metabolism; oncogenesis; reactive oxygen species
    DOI:  https://doi.org/10.3390/ijms23052702
  2. Diabetes. 2022 Mar 11. pii: db211079. [Epub ahead of print]
    Independent of Renox, NOX5 Promotes Renal Inflammation and Fibrosis in Diabetes by Activating ROS-sensitive Pathways.
    Jay C Jha, Aozhi Dai, Jessica Garzarella, Amelia Charlton, Sofia Urner, Jakob A Østergaard, Jun Okabe, Chet E Holterman, Alison Skene, David A Power, Elif I Ekinci, Melinda T Coughlan, Harald H H W Schmidt, Mark E Cooper, Rhian M Touyz, Chris R Kennedy, Karin Jandeleit-Dahm.
      Excessive production of renal reactive oxygen species (ROS) play a major role in diabetic kidney disease (DKD). Here, we provide key novel findings demonstrating the predominant pathological role of the prooxidant enzyme NADPH oxidase-NOX5 in DKD, independent of the previously characterised NOX4 pathway. In diabetic patients, we found increased expression of renal NOX5 in association with enhanced ROS formation and upregulation of ROS-sensitive factors EGR-1 (early growth response 1), PKC-α (protein kinase C- α) and a key metabolic gene involved in redox balance, TXNIP (thioredoxin-interacting protein). In preclinical models of DKD, overexpression of NOX5 in Nox4 deficient mice enhances kidney damage by increasing albuminuria and augmenting renal fibrosis and inflammation via enhanced ROS formation and the modulation of EGR1, TXNIP, ERK1/2, PKC-α and PKC-ε. In addition, the only first in class NOX inhibitor, GKT137831 appears to be ineffective in the presence of NOX5 expression in diabetes. In vitro, silencing of NOX5 in human mesangial cells attenuated high glucose induced upregulation of EGR1, PKC-α, and TXNIP as well as markers of inflammation (TLR4 and MCP-1) and fibrosis (CTGF and collagens I and III) via reduction in ROS formation. Collectively, these findings identify NOX5 as a superior target in human DKD compared to other NOX isoforms such as NOX4 which may have been overinterpreted in previous rodent studies.
    DOI:  https://doi.org/10.2337/db21-1079
  3. Redox Biol. 2022 Mar 03. pii: S2213-2317(22)00041-6. [Epub ahead of print]51 102269
    Inhibition of endothelial Nox2 activation by LMH001 protects mice from angiotensin II-induced vascular oxidative stress, hypertension and aortic aneurysm.
    Lampson M Fan, Fangfei Liu, Junjie Du, Li Geng, Jian-Mei Li.
      Endothelial oxidative stress and inflammation attributable to the activation of a Nox2-NADPH oxidase are key features of many cardiovascular diseases. Here, we report a novel small chemical compound (LMH001, MW = 290.079), by blocking phosphorylated p47phox interaction with p22phox, inhibited effectively angiotensin II (AngII)-induced endothelial Nox2 activation and superoxide production at a small dose (IC50 = 0.25 μM) without effect on peripheral leucocyte oxidative response to pathogens. The therapeutic potential of LMH001 was tested using a mouse model (C57BL/6J, 7-month-old) of AngII infusion (0.8 mg/kg/d, 14 days)-induced vascular oxidative stress, hypertension and aortic aneurysm. Age-matched littermates of p47phox knockout mice were used as controls of Nox2 inhibition. LMH001 (2.5 mg/kg/d, ip. once) showed no effect on control mice, but inhibited completely AngII infusion-induced excess ROS production in vital organs, hypertension, aortic walls inflammation and reduced incidences of aortic aneurysm. LMH001 effects on reducing vascular oxidative stress was due to its inhibition of Nox2 activation and was abrogated by knockout of p47phox. LMH001 has the potential to be developed as a novel drug candidate to treat oxidative stress-related cardiovascular diseases.
    Keywords:  Angiotensin II; Aortic aneurysm; Hypertension; Nox2 inhibitor; Vascular oxidative stress
    DOI:  https://doi.org/10.1016/j.redox.2022.102269
  4. Oxid Med Cell Longev. 2022 ;2022 1193734
    Inhibition of the NADPH Oxidase Pathway Reduces Ferroptosis during Septic Renal Injury in Diabetic Mice.
    Weifeng Yao, Haofeng Liao, Mengya Pang, Lijie Pan, Yu Guan, Xiaolei Huang, Ziqing Hei, Chenfang Luo, Mian Ge.
       Background: Obesity and type 2 diabetes mellitus (DM) contribute to a higher mortality rate in patients with septic acute kidney injury (AKI) during sepsis. Reactive oxygen species (ROS) is the major injury factor for sepsis. This study was aimed at exploring the potential therapeutic drug for septic AKI targeting on ROS.
    Methods: A murine septic AKI model was established in both wild-type and high-fat diet-fed (HFD) mice. NADPH oxidase inhibitor Vas2870 was used in vivo to explore the role of NADPH oxidase in ROS release in septic AKI in diabetic mice. Ferrostatin-1 was administered to investigate the role of ferroptosis in ROS accumulation during NADPH oxidase activating in septic AKI in diabetic mice.
    Results: Compared to chow diet-fed mice, HFD diabetic mice which were subjected to LPS exhibited aggravated renal function (blood urea nitrogen, creatinine clearance, and serum cystatin C) and oxidative stress (malondialdehyde, 4-HNE, ROS, 8-OHdG, and NADPH oxidase), thus resulting in a higher mortality rate. Septic renal injury was significantly attenuated by the ferroptosis inhibitor Fer-1 in HFD-challenged mice. Furthermore, ferroptosis accumulation and related protein expression (ASCL4, FTH1, and GPX4) were altered by LPS stimulation in HFD-challenged mice and suppressed by NADPH oxidase inhibition via Vas2870 in vivo. In summary, NADPH inhibition restored septic renal function from injury by suppressing ferroptosis accumulation in HFD-challenged mice.
    Conclusion: These results suggest that targeting NADPH-mediated ROS release and ferroptosis accumulation is a novel therapeutic strategy to protect the kidney from septic injury in patients with obesity and type 2 DM.
    DOI:  https://doi.org/10.1155/2022/1193734
  5. Front Cell Dev Biol. 2022 ;10 832314
    NADPH Oxidase 3 Deficiency Protects From Noise-Induced Sensorineural Hearing Loss.
    Francis Rousset, German Nacher-Soler, Vivianne Beatrix Christina Kokje, Stéphanie Sgroi, Marta Coelho, Karl-Heinz Krause, Pascal Senn.
      The reactive oxygen species (ROS)-generating NADPH oxidase NOX3 isoform is highly and specifically expressed in the inner ear. NOX3 is needed for normal vestibular development but NOX-derived ROS have also been implicated in the pathophysiology of sensorineural hearing loss. The role of NOX-derived ROS in noise-induced hearing loss, however, remains unclear and was addressed with the present study. Two different mouse strains, deficient in NOX3 or its critical subunit p22phox, were subjected to a single noise exposure of 2 h using an 8-16 kHz band noise at an intensity of 116-120 decibel sound pressure level. In the hours following noise exposure, there was a significant increase in cochlear mRNA expression of NOX3 in wild type animals. By using RNAscope in situ hybridization, NOX3 expression was primarily found in the Rosenthal canal area, colocalizing with auditory neurons. One day after the noise trauma, we observed a high frequency hearing loss in both knock-out mice, as well as their wild type littermates. At day seven after noise trauma however, NOX3 and p22phox knockout mice showed a significantly improved hearing recovery and a marked preservation of neurosensory cochlear structures compared to their wild type littermates. Based on these findings, an active role of NOX3 in the pathophysiology of noise-induced hearing loss can be demonstrated, in line with recent evidence obtained in other forms of acquired hearing loss. The present data demonstrates that the absence of functional NOX3 enhances the hearing recovery phase following noise trauma. This opens an interesting clinical window for pharmacological or molecular intervention aiming at post prevention of noise-induced hearing loss.
    Keywords:  NADPH oxidase; NOX3; auditory neurons; cochlea; neuroprotection; noise-induced hearing loss
    DOI:  https://doi.org/10.3389/fcell.2022.832314
  6. Dis Markers. 2022 ;2022 8567642
    Prognostic Value of NOX4 Expression in Cancer Patients: A Systematic Review and Meta-analysis.
    Hyun Min Koh, Bo Gun Jang, Chang Lim Hyun, Dong Chul Kim.
       Background: Recent studies have shown that nicotinamide adenosine dinucleotide phosphate oxidase 4 (NOX4) is related to cancer development, proliferation, invasion, epithelial-to-mesenchymal transition, and metastasis. The prognostic value of NOX4 expression although has been reported in various cancers, it remains unclear as several studies have reported conflicting results. Therefore, the purpose of this study was to systematically investigate the prognostic value of NOX4 expression in cancer patients.
    Method: Appropriate studies were collected by searching the PubMed, EMBASE, and Cochrane library databases, and the prognostic value of NOX4 expression in cancer patients was assessed through a meta-analysis.
    Results: Nine eligible studies involving 2675 cancer patients were included in this meta-analysis. We found that NOX4 expression is related to prognosis in cancer patients. In particular, high expression of NOX4 was significantly associated with overall survival in patients with gastrointestinal cancer (hazard ratio [HR]: 1.83, 95% confidence interval [CI]: 1.39-2.42, p < 0.001).
    Conclusion: NOX4 expression is significantly correlated with overall survival in patients with gastrointestinal cancer, indicating that it could be a potential prognostic marker.
    DOI:  https://doi.org/10.1155/2022/8567642
  7. Int J Mol Sci. 2022 Feb 28. pii: 2691. [Epub ahead of print]23(5):
    Diesel Particulate Extract Accelerates Premature Skin Aging in Human Fibroblasts via Ceramide-1-Phosphate-Mediated Signaling Pathway.
    Kyong-Oh Shin, Yoshikazu Uchida, Kyungho Park.
      Both intrinsic (i.e., an individual's body clock) and extrinsic factors (i.e., air pollutants and ultraviolet irradiation) accelerate premature aging. Epidemiological studies have shown a correlation between pollutant levels and aging skin symptoms. Diesel particle matter in particular leads to some diseases, including in the skin. Our recent study demonstrates that diesel particulate extract (DPE) increases apoptosis via increases in an anti-mitogenic/pro-apoptotic lipid mediator, ceramide in epidermal keratinocytes. Here, we investigated whether and how DPE accelerates premature skin aging using cultured normal human dermal fibroblasts (HDF). We first demonstrated that DPE increases cell senescence marker β-galactosidase activity in HDF. We then found increases in mRNA and protein levels, along with activity of matrix metalloprotease (MMP)-1 and MMP-3, which are associated with skin aging following DPE exposure. We confirmed increases in collagen degradation in HDF treated with DPE. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) is activated by DPE and results in increased ceramide production by sphingomyelinase activation in HDF. We identified that ceramide-1-phosphate (C1P) (produced from ceramide by ceramide kinase activation) activates MMP-1 and MMP-3 through activation of arachidonate cascade, followed by STAT 1- and STAT 3-dependent transcriptional activation.
    Keywords:  aging; ceramide; ceramide-1-phosphate; diesel particulate extract; matrix metalloprotease; skin
    DOI:  https://doi.org/10.3390/ijms23052691
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