NOX4 promotes non-small cell lung cancer cell proliferation and metastasis through positive feedback regulation of PI3K/Akt signaling

Zhang, Cuixiang; Lan, Tian; Hou, Jincai; Li, Juan; Fang, Rende; Yang, Zhicheng; Zhang, Min; Liu, Jianxun; Liu, Bing

doi:10.18632/oncotarget.2025

Cited by 97 publications

(98 citation statements)

References 35 publications

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“…The stimulus for peritoneal NOX4 overexpression during nephrotic syndrome remains to be determined. However, once it is triggered, overexpression of NOX4 might be maintained through positive feedback regulation because we showed that ROS activate NF-B, which in turn may induce NOX4 (24). NF-B may also exert a positive feedback on hydrogen peroxide levels by promoting SOD production (25).…”

Section: Discussionmentioning

confidence: 89%

Oxidative Stress and Nuclear Factor κB (NF-κB) Increase Peritoneal Filtration and Contribute to Ascites Formation in Nephrotic Syndrome

Udwan

Brideau

Fila

et al. 2016

Journal of Biological Chemistry

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Water accumulation in the interstitium (edema) and the peritoneum (ascites) of nephrotic patients is classically thought to stem from the prevailing low plasma albumin concentration and the decreased transcapillary oncotic pressure gradient. However, several clinical and experimental observations suggest that it might also stem from changes in capillary permeability. We addressed this hypothesis by studying the peritoneum permeability of rats with puromycin aminonucleosideinduced nephrotic syndrome. The peritoneum of puromycin aminonucleoside rats displayed an increase in the water filtration coefficient of paracellular and transcellular pathways, and a decrease in the reflection coefficient to proteins. It also displayed oxidative stress and subsequent activation of NF-B. Scavenging of reactive oxygen species and inhibition of NF-B prevented the changes in the water permeability and reflection coefficient to proteins and reduced the volume of ascites by over 50%. Changes in water permeability were associated with the overexpression of the water channel aquaporin 1, which was prevented by reactive oxygen species scavenging and inhibition of NF-B. In conclusion, nephrotic syndrome is associated with an increased filtration coefficient of the peritoneum and a decreased reflection coefficient to proteins. These changes, which account for over half of ascite volume, are triggered by oxidative stress and subsequent activation of NF-B. Nephrotic syndrome (NS)3 is a multifactorial glomerular disease defined by massive proteinuria and hypoalbuminemia. Irrespective of its etiology, NS is commonly associated with renal retention of sodium leading to the generation of ascites and/or edema (1, 2). Association of sodium retention with edema rather than with hypertension suggests that fluid flux across the capillary endothelium increases, and accordingly the capillary filtration capacity is 2-fold higher in nephrotic patients (3). Classically, this increase is thought to stem from hypoalbuminemia and a decreased oncotic gradient across the capillary wall. However, several observations militate against this theory: 1) the transcapillary gradient of oncotic pressure is almost unchanged in nephrotic patients (4, 5); 2) during steroid-induced remission of nephrotic syndrome, natriuresis resumes and edema decreases before normalization of serum albumin levels (6); and 3) diuretic treatments reduce edema without significantly changing the oncotic pressure gradient (5). Consequently, a new concept has emerged according to which the asymmetry of volume expansion in NS results from alterations of the intrinsic properties of the endothelial filtration barrier, i.e. its water permeability and/or its reflection coefficient to proteins. However, this hypothesis has not been demonstrated experimentally, and neither the molecular basis of these capillary alterations nor their connection to proteinuria and/or hypoalbuminemia is elucidated. Several studies have highlighted the pathophysiological importance of reactive oxygen species (ROS) in ...

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Section: Discussionmentioning

confidence: 89%

Oxidative Stress and Nuclear Factor κB (NF-κB) Increase Peritoneal Filtration and Contribute to Ascites Formation in Nephrotic Syndrome

Udwan

Brideau

Fila

et al. 2016

Journal of Biological Chemistry

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“…In cancer cell lines, elevated levels of NOX4 are associated with PI3K/Akt-regulated cell proliferation and invasion [99], TGF-β/SMAD3-driven EMT and cell migration [95], as well as Tks5-dependent invadopodia formation [80]. Depletion of NOX4 with siRNA treatment significantly reduced tumor growth in the in vivo models of bladder cancer [75], renal cancer [100], and glioblastoma [57].…”

Section: Nox4 – the Main Source Of Ros In Fibrosis And Cancermentioning

confidence: 99%

“…Some issues with specificity, potency, and toxicity of these inhibitors have limited the use of these compounds in clinical studies [148]. Gene silencing of NOXes has been carried out with shRNA and siRNA [75], [99], [149] but primarily as a proof-of-concept in in vivo studies without using suitable delivery agents such as liposomes or nanoparticles to safely and efficiently deliver these molecules to the right target. The different types of NOX inhibitors as well as NOX gene therapeutics, and their potential applications from the in-vivo studies are summarized in Table 3.…”

Section: Strategies To Suppress Oxidative Stressmentioning

confidence: 99%

Oxidative stress in cancer and fibrosis: Opportunity for therapeutic intervention with antioxidant compounds, enzymes, and nanoparticles

2017

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Oxidative stress, mainly contributed by reactive oxygen species (ROS), has been implicated in pathogenesis of several diseases. We review two primary examples; fibrosis and cancer. In fibrosis, ROS promote activation and proliferation of fibroblasts and myofibroblasts, activating TGF-β pathway in an autocrine manner. In cancer, ROS account for its genomic instability, resistance to apoptosis, proliferation, and angiogenesis. Importantly, ROS trigger cancer cell invasion through invadopodia formation as well as extravasation into a distant metastasis site. Use of antioxidant supplements, enzymes, and inhibitors for ROS-generating NADPH oxidases (NOX) is a logical therapeutic intervention for fibrosis and cancer. We review such attempts, progress, and challenges. Lastly, we review how nanoparticles with inherent antioxidant activity can also be a promising therapeutic option, considering their additional feature as a delivery platform for drugs, genes, and imaging agents.

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“…Activation of the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling pathway indicates poor patient prognosis and is associated with different types of cancer, including NSCLC, prostate and breast cancer (16)(17)(18). Furthermore, activation of the PI3K/Akt signaling pathway may promote tumor cell proliferation, migration and drug resistance (19).…”

Section: Introductionmentioning

confidence: 99%

Oncogenic activity of insulin in the development of non‑small cell lung carcinoma

et al. 2017

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Abstract. Insulin is associated with the progression of numerous different types of cancer. However, the association between insulin and non-small cell lung carcinoma (NSCLC) remains unknown. The aim of the present study was to evaluate the role of insulin in the proliferation, migration and drug resistance of NSCLC cells, and to determine whether the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathway was involved. NSCLC cells were treated with insulin in the absence or presence of LY294002, an inhibitor of the PI3K/Akt pathway. Following co-incubation with insulin, cell proliferation and drug resistance were measured by MTT; cell migration was examined by wound healing and Transwell assays; and the expression of cyclin A, proliferating cell nuclear antigen (PCNA), p27, matrix metalloproteinase 3 (MMP3), P-gp and proteins involved in the PI3K/Akt pathway were assessed via western blotting. The results of the current study demonstrated that insulin enhanced the proliferation, migration and drug resistance of NSCLC cells. Correspondingly, insulin upregulated the expression of cyclin A, PCNA, MMP3, P-gp and downregulated p27 expression in NSCLC cells. Following treatment with insulin, it was demonstrated that phospho-Akt expression increased in a dose-dependent manner. However, the effects of insulin on NSCLC cells was inhibited by the PI3K/Akt pathway inhibitor LY294002. Therefore, the results of the current study indicate that insulin is associated with the development of NSCLC by activating the PI3K/Akt pathway. This may improve understanding of the mechanism of action of insulin in NSCLC in the future.

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NOX4 promotes non-small cell lung cancer cell proliferation and metastasis through positive feedback regulation of PI3K/Akt signaling

Cited by 97 publications

References 35 publications

Oxidative Stress and Nuclear Factor κB (NF-κB) Increase Peritoneal Filtration and Contribute to Ascites Formation in Nephrotic Syndrome

Oxidative Stress and Nuclear Factor κB (NF-κB) Increase Peritoneal Filtration and Contribute to Ascites Formation in Nephrotic Syndrome

Oxidative stress in cancer and fibrosis: Opportunity for therapeutic intervention with antioxidant compounds, enzymes, and nanoparticles

Oncogenic activity of insulin in the development of non‑small cell lung carcinoma

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