Nox4-dependent ROS modulation by amino endoperoxides to induce apoptosis in cancer cells

Zhu, Pengcheng; Tong, Benny Meng Kiat; Wang, Runze; Chen, Jiapeng; Foo, Selin; Chong, Han Chung; Wang, Xiao Ling; Ang, Gim Yean; Chiba, Shunsuke; Tan, Nguan Soon

doi:10.1038/cddis.2013.68

Cited by 28 publications

(21 citation statements)

References 41 publications

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“…Nox4, a member of the NOX family of NADPH oxidases, is responsible for the production of large amounts of ROS [20]. It was reported that Nox4-dependent ROS modulation can induce apoptosis in high Nox4-expressing cancer cells [18]. In our study, increased ROS was detected in PA-treated AML12 cells.…”

Section: Discussionsupporting

confidence: 59%

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ShenFu Preparation Protects AML12 Cells Against Palmitic Acid-Induced Injury Through Inhibition of Both JNK/Nox4 and JNK/NFκB Pathways

Ji¹,

Jiao

Chen

et al. 2018

Cell Physiol Biochem

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Background/Aims: Nonalcoholic steatohepatitis includes steatosis along with liver inflammation, hepatocyte injury and fibrosis. In this study, we investigated the protective role and the potential mechanisms of a traditional Chinese medicine ShenFu (SF) preparation in an in vitro hepatic steatosis model. Methods: In palmitic acid (PA)-induced murine hepatic AML12 cell injury, effects of SF preparation on cellular apoptosis and intracellular triglyceride (iTG) level were assessed using TUNEL and TG Colorimetric Assay. Reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) levels were measured using DCF and JC-1 assay. Cytokine levels were evaluated using ELISA assay. Immunoblot was used to compare the activation level of c-Jun N terminal kinase (JNK), NADPH oxidase (Nox4), and NFκB pathways. Results: Addition of SF preparation prevented PA-mediated increase of apoptosis and iTG as well as IL-8 and IL-6. In PA-treated cell, SF preparation reduced the level of Nox4 and ROS, while increasing the level of MMP and the expression of manganese superoxide dismutase (MnSOD) and catalase, indicating emendation of mitochondrial dysfunction. Nox4 inhibitor GKT137381 prevented PA-induced increase of ROS and apoptosis, while decreasing iTG slightly and not influencing the level of IL-8 and IL-6. SF preparation prevented PA-induced upregulation of phospho-JNK. JNK inhibitor SP600125 prevented PA-mediated increase of Nox4, IL-8, IL-6 and iTG. Nuclear translocation of NFκB/p65 was detected in PA-treated cells, which was prevented by SF preparation. An IκB degradation inhibitor, BAY11-7082, prevented PA-induced increase of IL-8 and IL-6 as well as iTG, whereas it only decreased ROS levels slightly and showed no influence on cellular apoptosis. Conclusion: SF preparation shows a beneficial role in prevention of hepatocyte injury by attenuating oxidative stress and cytokines production at least partially through inhibition of JNK/Nox4 and JNK/NFκB pathway, respectively.

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Section: Discussionsupporting

confidence: 59%

“…Routinely, mitochondrial dysfunction, particularly the increased Nox4, leads to oxidative stress [18]. Here, the reactive oxygen species (ROS) level was investigated using DCF assay.…”

Section: Resultsmentioning

confidence: 99%

ShenFu Preparation Protects AML12 Cells Against Palmitic Acid-Induced Injury Through Inhibition of Both JNK/Nox4 and JNK/NFκB Pathways

Ji¹,

Jiao

Chen

et al. 2018

Cell Physiol Biochem

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“…S7D). Three other NOX4 inhibiting compounds, imipramine blue, an aminoendoperoxide designated 4-Me (48,49), and GKT137831, an orally available dual NOX1/4 inhibitor (50), which became recently commercially available, likewise inhibited growth of FLT3ITD transformed cells in a dose-dependent manner ( Fig. S7E-H).…”

Section: Nox4 Is Important For Flt3itd-mediated Cell Transformation Imentioning

confidence: 88%

NOX4-driven ROS formation mediates PTP inactivation and cell transformation in FLT3ITD-positive AML cells

et al. 2015

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Activating mutations of FMS-like tyrosine kinase 3 (FLT3), notably internal tandem duplications (ITDs), are associated with a grave prognosis in acute myeloid leukemia (AML). Transforming FLT3ITD signal transduction causes formation of reactive oxygen species (ROS) and inactivation of the protein-tyrosine phosphatase (PTP) DEP-1/PTPRJ, a negative regulator of FLT3 signaling. Here we addressed the underlying mechanisms and biological consequences. NADPH oxidase 4 (NOX4) messenger RNA and protein expression was found to be elevated in FLT3ITD-positive cells and to depend on FLT3ITD signaling and STAT5-mediated activation of the NOX4 promoter. NOX4 knockdown reduced ROS levels, restored DEP-1 PTP activity and attenuated FLT3ITD-driven transformation. Moreover, Nox4 knockout (Nox4(-/-)) murine hematopoietic progenitor cells were refractory to FLT3ITD-mediated transformation in vitro. Development of a myeloproliferative-like disease (MPD) caused by FLT3ITD-transformed 32D cells in C3H/HeJ mice, and of a leukemia-like disease in mice transplanted with MLL-AF9/ FLT3ITD-transformed murine hematopoietic stem cells were strongly attenuated by NOX4 downregulation. NOX4-targeting compounds were found to counteract proliferation of FLT3ITD-positive AML blasts and MPD development in mice. These findings reveal a previously unrecognized mechanism of oncoprotein-driven PTP oxidation, and suggest that interference with FLT3ITD-STAT5-NOX4-mediated overproduction of ROS and PTP inactivation may have therapeutic potential in a subset of AML.

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“…From the Venn Diagram shown in Fig.3, only “NOX4” [38] is selected in both DNA methylation and gene expression profiles. Note that, gene expression and DNA methylation may be correlated.…”

Section: Tests On Real Datamentioning

confidence: 99%

Cancer Progression Prediction Using Gene Interaction Regularized Elastic Net

Zhang

Liu

Huang

et al. 2017

IEEE/ACM Trans. Comput. Biol. and Bioinf.

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Different types of genomic aberration may simultaneously contribute to tumorigenesis. To obtain a more accurate prognostic assessment to guide therapeutic regimen choice for cancer patients, the heterogeneous multi-omic data should be integrated harmoniously, which can often be difficult. For this purpose, we propose a Gene Interaction Regularized Elastic Net (GIREN) model that predicts clinical outcome by integrating multiple data types. GIREN conveniently embraces both gene measurements and gene-gene interaction information under an elastic net formulation, enforcing structure sparsity and the “grouping effect” in solution to select the discriminate features with prognostic value. An iterative gradient descent algorithm is also developed to solve the model with regularized optimization. GIREN was applied to human ovarian cancer and breast cancer datasets obtained from The Cancer Genome Atlas, respectively. Result shows that, the proposed GIREN algorithm obtained more accurate and robust performance over competing algorithms (LASSO, Elastic Net and superPC, with or without average pathway expression features) in predicting cancer progression on both two datasets in terms of median Area Under Curve (AUC) and Interquartile Range (IQR), suggesting a promising direction for more effective integration of gene measurement and gene interaction information.

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Nox4-dependent ROS modulation by amino endoperoxides to induce apoptosis in cancer cells

Cited by 28 publications

References 41 publications

ShenFu Preparation Protects AML12 Cells Against Palmitic Acid-Induced Injury Through Inhibition of Both JNK/Nox4 and JNK/NFκB Pathways

ShenFu Preparation Protects AML12 Cells Against Palmitic Acid-Induced Injury Through Inhibition of Both JNK/Nox4 and JNK/NFκB Pathways

NOX4-driven ROS formation mediates PTP inactivation and cell transformation in FLT3ITD-positive AML cells

Cancer Progression Prediction Using Gene Interaction Regularized Elastic Net

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