bims-noxint 2021-11-07 papers

Issue of 2021–11–07
four papers selected by
Laia Caja Puigsubira, Uppsala University

BMC Cancer. 2021 Nov 05. 21(1): 1181

NOX4-derived ROS-induced overexpression of FOXM1 regulates aerobic glycolysis in glioblastoma.

Xiangsheng Su, Yihang Yang, Qing Yang, Bo Pang, Shicheng Sun, Yanjun Wang, Qiujiang Qiao, Changfa Guo, Huanting Liu, Qi Pang.

BACKGROUND: Increased expression of the transcription factor Forkhead box M1 (FOXM1) has been reported to play an important role in the progression and development of multiple tumors, but the molecular mechanisms that regulate FOXM1 expression remain unknown, and the role of FOXM1 in aerobic glycolysis is still not clear.
METHODS: The expression of FOXM1 and NADPH oxidase 4 (NOX4) in normal brain tissues and glioma was detected in data from the TCGA database and in our specimens. The effect of NOX4 on the expression of FOXM1 was determined by Western blot, qPCR, reactive oxygen species (ROS) production assays, and luciferase assays. The functions of NOX4 and FOXM1 in aerobic glycolysis in glioblastoma cells were determined by a series of experiments, such as Western blot, extracellular acidification rate (ECAR), lactate production, and intracellular ATP level assays. A xenograft mouse model was established to test our findings in vivo.
RESULTS: The expression of FOXM1 and NOX4 was increased in glioma specimens compared with normal brain tissues and correlated with poor clinical outcomes. Aberrant mitochondrial reactive oxygen species (ROS) generation of NOX4 induced FOXM1 expression. Mechanistic studies demonstrated that NOX4-derived MitoROS exert their regulatory role on FOXM1 by mediating hypoxia-inducible factor 1α (HIF-1α) stabilization. Further research showed that NOX4-derived MitoROS-induced HIF-1α directly activates the transcription of FOXM1 and results in increased FOXM1 expression. Overexpression of NOX4 or FOXM1 promoted aerobic glycolysis, whereas knockdown of NOX4 or FOXM1 significantly suppressed aerobic glycolysis, in glioblastoma cells. NOX4-induced aerobic glycolysis was dependent on elevated FOXM1 expression, as FOXM1 knockdown abolished NOX4-induced aerobic glycolysis in glioblastoma cells both in vitro and in vivo.
CONCLUSION: Increased expression of FOXM1 induced by NOX4-derived MitoROS plays a pivotal role in aerobic glycolysis, and our findings suggest that inhibition of NOX4-FOXM1 signaling may present a potential therapeutic target for glioblastoma treatment.

Keywords: Aerobic glycolysis; FOXM1; Glioblastoma; NOX4; ROS

DOI: https://doi.org/10.1186/s12885-021-08933-y

Redox Biol. 2021 Sep 23. pii: S2213-2317(21)00308-6. [Epub ahead of print]48 102148

Novel mechanisms in alcohol neurodevelopmental disorders via BRCA1 depletion and BRCA1-dependent NADPH oxidase regulation.

Danielle M Drake, Peter G Wells.

The breast cancer 1 protein (BRCA1) facilitates DNA repair, preventing embryolethality and protecting the fetus from reactive oxygen species (ROS)-induced developmental disorders mediated by oxidatively damaged DNA. Alcohol (ethanol, EtOH) exposure during pregnancy causes fetal alcohol spectrum disorders (FASD), characterized by aberrant behaviour and enhanced ROS formation and proteasomal protein degradation. Herein, ROS-producing NADPH oxidase (NOX) activity was higher in Brca1 +/- vs. +/+ fetal and adult brains, and further enhanced by a single EtOH exposure. EtOH also enhanced catalase and proteasomal activities, while conversely reducing BRCA1 protein levels without affecting Brca1 gene expression. EtOH-initiated adaptive postnatal freezing behaviour was lost in Brca1 +/- progeny. Pretreatment with the free radical spin trap and ROS inhibitor phenylbutylnitrone blocked all EtOH effects, suggesting ROS-dependent mechanisms. This is the first in vivo evidence of NOX regulation by BRCA1, and of EtOH-induced, ROS-mediated depletion of BRCA1, revealing novel mechanisms of BRCA1 protection in FASD.

Keywords: Breast cancer 1 susceptibility gene (Brca1); Catalase; Fear conditioning; NADPH oxidase (NOX); Neurodevelopmental disorders; Proteasomal activity

DOI: https://doi.org/10.1016/j.redox.2021.102148

Front Immunol. 2021 ;12 730672

Production of IL-6 and Phagocytosis Are the Most Resilient Immune Functions in Metabolically Compromised Human Monocytes.

Pierre-Louis Krauss, Moritz Pfeiffenberger, Alexandra Damerau, Thomas Buttgereit, Yuling Chen, Timo Gaber, Frank Buttgereit.

At sites of inflammation, monocytes carry out specific immune functions while facing challenging metabolic restrictions. Here, we investigated the potential of human monocytes to adapt to conditions of gradually inhibited oxidative phosphorylation (OXPHOS) under glucose free conditions. We used myxothiazol, an inhibitor of mitochondrial respiration, to adjust two different levels of decreased mitochondrial ATP production. At these levels, and compared to uninhibited OXPHOS, we assessed phagocytosis, production of reactive oxygen species (ROS) through NADPH oxidase (NOX), expression of surface activation markers CD16, CD80, CD11b, HLA-DR, and production of the inflammatory cytokines IL-1β, IL-6 and TNF-α in human monocytes. We found phagocytosis and the production of IL-6 to be least sensitive to metabolic restrictions while surface expression of CD11b, HLA-DR, production of TNF-α, IL-1β and production of ROS through NOX were most compromised by inhibition of OXPHOS in the absence of glucose. Our data demonstrate a short-term hierarchy of immune functions in human monocytes, which represents novel knowledge potentially leading to the development of new therapeutics in monocyte-mediated inflammatory diseases.

Keywords: ATP; IL-6; bioenergetics; energy; human monocytes; immunometabolism; lack of glucose availability; phagocytosis

DOI: https://doi.org/10.3389/fimmu.2021.730672

Sci Total Environ. 2021 Oct 27. pii: S0048-9697(21)06196-9. [Epub ahead of print] 151118

Redox sensitive miR-27a/b/Nrf2 signaling in Cr(VI)-induced carcinogenesis.

Lin Wang, Khaliunaa Bayanbold, Lei Zhao, Yifang Wang, Andrea Adamcakova-Dodd, Peter S Thorne, Hushan Yang, Bing-Hua Jiang, Ling-Zhi Liu.

Hexavalent chromium [Cr(VI)] is a well-known carcinogen that can cause several types of cancer including lung cancer. NF-E2-related factor 2 (Nrf2), the redox sensitive transcription factor, can protect normal cells from a variety of toxicants and carcinogens by inducing the expression of cellular protective genes and maintaining redox balance. However, Nrf2 also protects cancer cells from radio- and chemo-therapies and facilitates cancer progression. Although Cr(VI) treatment has been demonstrated to upregulate Nrf2 expression, the mechanisms for Nrf2 regulation upon chronic Cr(VI) exposure remain to be elucidated. We found that Nrf2 was upregulated in BEAS-2B cells exposed to Cr(VI) from 1 to 5 months, and also in Cr(VI)-induced transformed (Cr-T) cells with Cr(VI) treatment for 6 months. We showed that KEAP1, the classic negative regulator of Nrf2, was downregulated after Cr(VI) exposure for 4 months, suggesting that Nrf2 induction by Cr(VI) treatment is through KEAP1 decrease at late stage. To further decipher the mechanisms of Nrf2 upregulation at early stage of Cr(VI) exposure, we demonstrated that miR-27a and miR-27b were redox sensitive miRNAs, since reactive oxygen species (ROS) scavengers induced miR-27a/b expression. After Cr(VI) exposure for 1 month, the expression levels of miR-27a/b was dramatically decreased. The changes of miR-27a/b and their target Nrf2 were confirmed in vivo by mouse model intranasally exposed to Cr(VI) for 12 weeks. Nrf2 was a direct target of miR-27a/b, which acted as tumor suppressors in vitro and in vivo to inhibit tumorigenesis and cancer development of Cr-T cells. The results suggested that the inhibition of miR-27a/b was responsible for Nrf2 upregulation at both early stage and late stage of Cr(VI) exposure. This novel regulation of Nrf2 upon chronic Cr(VI) exposure through redox-regulated miR-27a/b will provide potential targets for preventing and treating Cr(VI)-induced carcinogenesis in the future.

Keywords: Chromium (VI); Lung cancer; Nrf2; Tumor growth; miR-27a/b

DOI: https://doi.org/10.1016/j.scitotenv.2021.151118