bims-noxint 2019-07-21 papers

bims-noxint

Biomed News

on NADPH oxidases in tumorigenesis

Issue of 2019–07–21
six papers selected by
Laia Caja Puigsubira, Uppsala University

Reactive oxygen species induce epithelial‑mesenchymal transition, glycolytic switch, and mitochondrial repression through the Dlx‑2/Snail signaling pathways in MCF‑7 cells.
Redox signals at the ER-mitochondria interface control melanoma progression.
NADPH oxidase 4 is correlated with gastric cancer progression and predicts a poor prognosis.
Connexin43 contributes to inflammasome activation and LPS-initiated acute renal injury via modulation of intracellular oxidative status.
The phagocyte NOX2 NADPH oxidase in microbial killing and cell signaling.
Perturbation of ubiquitin homeostasis promotes macrophage oxidative defenses.

Mol Med Rep. 2019 Jul 03.

Reactive oxygen species induce epithelial‑mesenchymal transition, glycolytic switch, and mitochondrial repression through the Dlx‑2/Snail signaling pathways in MCF‑7 cells.

Su Yeon Lee, Min Kyung Ju, Hyun Min Jeon, Yig Ji Lee, Cho Hee Kim, Hye Gyeong Park, Song Iy Han, Ho Sung Kang.

Reactive oxygen species (ROS) are important cellular second messengers involved in various aspects of cell signaling. ROS are elevated in multiple types of cancer cells, and this elevation is known to be involved in pathological processes of cancer. Although high levels of ROS exert cytotoxic effects on cancer cells, low levels of ROS stimulate cell proliferation and survival by inducing several pro‑survival signaling pathways. In addition, ROS have been shown to induce epithelial‑mesenchymal transition (EMT), which is essential for the initiation of metastasis. However, the precise mechanism of ROS‑induced EMT remains to be elucidated. In the present study, it was indicated that ROS induce EMT by activating Snail expression, which then represses E‑cadherin expression in MCF‑7 cells. It was further indicated that distal‑less homeobox‑2 (Dlx‑2), one of the human Dlx gene family proteins involved in embryonic development, acts as an upstream regulator of ROS‑induced Snail expression. It was also revealed that ROS treatment induces the glycolytic switch, a phenomenon whereby cancer cells primarily rely on glycolysis instead of mitochondrial oxidative phosphorylation for ATP production, even in the presence of oxygen. In addition, ROS inhibited oxidative phosphorylation and caused cytochrome c oxidase inhibition via the Dlx‑2/Snail cascade. These results suggest that ROS induce EMT, the glycolytic switch and mitochondrial repression by activating the Dlx‑2/Snail axis, thereby playing crucial roles in MCF‑7 cancer cell progression.

DOI: https://doi.org/10.3892/mmr.2019.10466
EMBO J. 2019 Jul 15. e100871

Redox signals at the ER-mitochondria interface control melanoma progression.

Xin Zhang, Christine S Gibhardt, Thorsten Will, Hedwig Stanisz, Christina Körbel, Miso Mitkovski, Ioana Stejerean, Sabrina Cappello, David Pacheu-Grau, Jan Dudek, Nasser Tahbaz, Lucas Mina, Thomas Simmen, Matthias W Laschke, Michael D Menger, Michael P Schön, Volkhard Helms, Barbara A Niemeyer, Peter Rehling, Adina Vultur, Ivan Bogeski.

  Reactive oxygen species (ROS) are emerging as important regulators of cancer growth and metastatic spread. However, how cells integrate redox signals to affect cancer progression is not fully understood. Mitochondria are cellular redox hubs, which are highly regulated by interactions with neighboring organelles. Here, we investigated how ROS at the endoplasmic reticulum (ER)-mitochondria interface are generated and translated to affect melanoma outcome. We show that TMX1 and TMX3 oxidoreductases, which promote ER-mitochondria communication, are upregulated in melanoma cells and patient samples. TMX knockdown altered mitochondrial organization, enhanced bioenergetics, and elevated mitochondrial- and NOX4-derived ROS. The TMX-knockdown-induced oxidative stress suppressed melanoma proliferation, migration, and xenograft tumor growth by inhibiting NFAT1. Furthermore, we identified NFAT1-positive and NFAT1-negative melanoma subgroups, wherein NFAT1 expression correlates with melanoma stage and metastatic potential. Integrative bioinformatics revealed that genes coding for mitochondrial- and redox-related proteins are under NFAT1 control and indicated that TMX1, TMX3, and NFAT1 are associated with poor disease outcome. Our study unravels a novel redox-controlled ER-mitochondria-NFAT1 signaling loop that regulates melanoma pathobiology and provides biomarkers indicative of aggressive disease.

Keywords:  calcium; contact site; melanoma; mitochondria; redox

DOI:  https://doi.org/10.15252/embj.2018100871
Am J Transl Res. 2019 ;11(6): 3518-3530

NADPH oxidase 4 is correlated with gastric cancer progression and predicts a poor prognosis.

Shangce Du, Ji Miao, Xiaofeng Lu, Linsen Shi, Jie Sun, En Xu, Xingzhou Wang, Min Zhao, Hong Chen, Feng Wang, Xin Kang, Jie Ding, Wenxian Guan, Xuefeng Xia.

NADPH oxidase 4 (NOX4) is one of the main sources of reactive oxygen species, and plays a crucial role in the occurrence and development of tumors. However, there is currently little evidence demonstrating that NOX4 expression is associated with gastric cancer. To establish whether NOX4 plays a role in gastric cancer progression and prognosis, we performed immunohistochemistry on gastric cancer tissues and paired adjacent normal tissues from 90 gastric cancer patients to detect and compare NOX4 expression. Next, we analyzed the association between NOX4 expression and clinicopathological characteristics. Survival analysis was performed to explore the association between NOX4 expression and the prognosis of gastric cancer patients. Furtherly, we investigated the effect of NOX4-knockdown using siRNA on gastric cancer progression in vitro and in vivo. Our results revealed that NOX4 expression in gastric cancer tissues is higher than in paired adjacent normal tissues (P = 0.0009). NOX4 expression is significantly correlated with tumor size (P = 0.0321), lymphatic metastasis (P = 0.0125) and vascular invasion (P = 0.0017) and a poor prognosis (P = 0.0000) in gastric cancer patients. NOX4 depletion could significantly inhibit the invasion, proliferation, EMT and MMP7 expression of gastric cancer cells and suppress the progression of gastric cancer in vivo. In conclusion, NOX4 is related to gastric cancer development and predicts a poor prognosis. NOX4 may play an essential role in the progression of gastric cancer, and is a promising target for the prevention and treatment of gastric cancer.

Keywords: NOX4; gastric cancer; prognosis; progression; reactive oxygen species
Antioxid Redox Signal. 2019 Jul 18.

Connexin43 contributes to inflammasome activation and LPS-initiated acute renal injury via modulation of intracellular oxidative status.

Yanru Huang, Zhimin Mao, Zhen Zhang, Fumiko Obata, Xiawen Yang, Xiling Zhang, Yong Huang, Takahiko Mitsui, Jianglin Fan, Masayuki Takeda, Jian Yao.

AIMS: Inflammasome activation plays a pivotal role in many inflammatory diseases. Given that connexin channels regulate numerous cellular events leading to inflammasome activation, we determined whether and how connexin affected inflammasome activation and inflammatory cell injury.
RESULTS: Exposure of mouse peritoneal macrophages (PMs) to LPS plus ATP caused NLRP3 inflammasome activation, together with an increased Cx43. Inhibition of Cx43 blunted inflammasome activation. Consistently, PMs from Cx43 heterozygous mouse (Cx43+/-) exhibited a weak inflammasome activation, in comparison with those from Cx43+/+ mouse. Further analysis revealed that inflammasome activation was preceded by an increased ROS production, NADPH oxidase 2 (NOX2), protein carbonylation and MAPK activation. Suppression of ROS with antioxidant, downregulation of NOX2 with siRNA, or inhibition of NADPH oxidase or MAPKs with inhibitors blocked Cx43 elevation and inflammasome activation. Intriguingly, suppression of Cx43 also blunted NOX2 expression, protein carbonylation, p38 phosphorylation and inflammasome activation. In a model of acute renal injury induced by LPS, Cx43+/- mouse exhibited a significantly lower level of blood IL-1β, blood urea nitrogen and urinary protein, together with milder renal pathological changes and renal expression of NLRP3 and NOX4, as compared with Cx43+/+ mouse. Moreover, inhibition of gap junctions suppressed IL-1β- and TNF-α-induced expression of NOX4 in glomerular podocytes and tubular epithelial cells. Innovation and conclusion: Our study indicates that Cx43 contributes to inflammasome activation and the progression of renal inflammatory cell injury through modulation of intracellular redox status. Cx43 could be a novel target for the treatment of certain inflammatory diseases.

DOI: https://doi.org/10.1089/ars.2018.7636
Curr Opin Immunol. 2019 Jul 10. pii: S0952-7915(18)30129-8. [Epub ahead of print]60 130-140

The phagocyte NOX2 NADPH oxidase in microbial killing and cell signaling.

William M Nauseef.

The phagocyte NADPH oxidase possesses a transmembrane electron transferase comprised of gp91phox (aka NOX2) and p22phox and two multicomponent cytosolic complexes, which in stimulated phagocytes translocate to assemble a functional enzyme complex at plasma or phagosomal membranes. The NOX2-centered NADPH oxidase shuttles electrons from cytoplasmic NADPH to molecular oxygen in phagosomes or the extracellular space to produce oxidants that support optimal antimicrobial activity by phagocytes. Additionally, NOX2-generated oxidants have been implicated in both autocrine and paracrine signaling in a variety of biological contexts. However, when interpreting experimental results, investigators must recognize the complexity inherent in the biochemistry of oxidant-mediated attack of microbial targets and the technical limitations of the probes currently used to detect intracellular oxidants.

DOI: https://doi.org/10.1016/j.coi.2019.05.006
Sci Rep. 2019 Jul 15. 9(1): 10245

Perturbation of ubiquitin homeostasis promotes macrophage oxidative defenses.

Marie-Eve Charbonneau, Karla D Passalacqua, Susan E Hagen, Hollis D Showalter, Christiane E Wobus, Mary X D O'Riordan.

The innate immune system senses microbial ligands through pattern recognition and triggers downstream signaling cascades to promote inflammation and immune defense mechanisms. Emerging evidence suggests that cells also recognize alterations in host processes induced by infection as triggers. Protein ubiquitination and deubiquitination are post-translational modification processes essential for signaling and maintenance of cellular homeostasis, and infections can cause global alterations in the host ubiquitin proteome. Here we used a chemical biology approach to perturb the cellular ubiquitin proteome as a simplified model to study the impact of ubiquitin homeostasis alteration on macrophage function. Perturbation of ubiquitin homeostasis led to a rapid and transient burst of reactive oxygen species (ROS) that promoted macrophage inflammatory and anti-infective capacity. Moreover, we found that ROS production was dependent on the NOX2 phagocyte NADPH oxidase. Global alteration of the ubiquitin proteome also enhanced proinflammatory cytokine production in mice stimulated with a sub-lethal dose of LPS. Collectively, our findings suggest that major changes in the host ubiquitin landscape may be a potent signal to rapidly deploy innate immune defenses.

DOI: https://doi.org/10.1038/s41598-019-46526-9