Aerobic glycolysis promotes tumor immune evasion by hexokinase2-mediated phosphorylation of IκBα

Guo, Dong; Tong, Yuru; Jiang, Xiaoming; Meng, Ying; Jiang, Hongfei; Du, Linyong; Wu, Qingang; Li, Shan; Luo, Shudi; Li, Min; Xiao, Liwei; He, Haiyan; He, Xuxiao; Yu, Qiujing; Fang, Jing; Lu, Zhimin

doi:10.1016/j.cmet.2022.08.002

Cited by 146 publications

(108 citation statements)

References 44 publications

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“…The first step of glycolysis is catalyzed by hexokinase (HK), which converts glucose to glucose-6-phosphate (G-6-P). Recent studies have shown that HK2 can promote tumour immune evasion by phosphorylating IκBα, leading to the degradation of IκBα, activation of the NF-κB signalling pathway, and elevated PD-L1 expression levels [ 26 ]. We showed that CSFV infection inhibits the rate of extracellular acidification and reduces the overall cellular glycolysis level.…”

Section: Resultsmentioning

confidence: 99%

The regulation of cell homeostasis and antiviral innate immunity by autophagy during classical swine fever virus infection

Song

Zhao

et al. 2023

Emerging Microbes & Infections

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CSFV (classical swine fever virus) is currently endemic in developing countries in Asia and has recently re-emerged in Japan. Under the pressure of natural selection pressure, CSFV keeps evolving to maintain its ecological niche in nature. CSFV has evolved mechanisms that induce immune depression, but its pathogenic mechanism is still unclear. In this study, using transcriptomics and metabolomics methods, we found that CSFV infection alters innate host immunity by activating the interferon pathway, inhibiting host inflammation, apoptosis, and remodelling host metabolism in porcine alveolar macrophages. Moreover, we revealed that autophagy could alter innate immunity and metabolism induced by CSFV infection. Enhanced autophagy further inhibited CSFV-induced RIG-I-IRF3 signal transduction axis and JAK-STAT signalling pathway and blocked type I interferon production while reducing autophagy inhibition of the NF-κB signalling pathway and apoptosis in CSFV infection cells. Furthermore, the level of CSFV infection-induced glycolysis and the content of lactate and pyruvate, as well as 3-phosphoglyceraldehyde, a derivative of glycolysis converted to serine, was altered by autophagy. We also found that silencing HK2 (hexokinase 2), the rate-limiting enzyme of glycolytic metabolism, could induce autophagy but reduce the interferon signalling pathway, NF-κB signalling pathway, and inhibition of apoptosis induced by CSFV infection. In addition, inhibited cellular autophagy by silencing ATG5 or using 3-Methyladenine, could backfill the inhibitory effect of silencing HK2 on the cellular interferon signalling pathway, NF-κB signalling pathway, and apoptosis.

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Section: Resultsmentioning

confidence: 99%

The regulation of cell homeostasis and antiviral innate immunity by autophagy during classical swine fever virus infection

Song

Zhao

et al. 2023

Emerging Microbes & Infections

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“…Recent studies demonstrated that increased lactic acid in the TME could suppress anticancer immune cells by disturbing their intracellular pH ( Frauwirth et al, 2002 ; Gottfried et al, 2006 ) and impair T cell proliferation and cytokine production ( Brand et al, 2016 ; Fischer et al, 2007 ). Furthermore, Guo et al (2022) revealed that tumor immune evasion can be directly regulated by availability of glucose in the TME. When cancer glycolytic activity competes with immune cells for glucose uptake ( Husain et al, 2013a ; Husain, Seth & Sukhatme, 2013b ), cancer cells could effectively achieve immune evasion.…”

Section: Discussionmentioning

confidence: 99%

OPA1 supports mitochondrial dynamics and immune evasion to CD8⁺ T cell in lung adenocarcinoma

Wang

Jiang

et al. 2022

PeerJ

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Background Mitochondrial fusion and fission were identified to play key roles during multiple biology process. Thus, we aim to investigate the roles of OPA1 in mitochondria fusion and immune evasion of non-small cell lung cancer cells. Methods The transcriptional activation of genes related to mitochondrial dynamics was determined by using multi-omics data in lung adenocarcinoma (LUAD). We elucidated the molecular mechanism and roles of OPA1 promoting lung cancer through single-cell sequencing and molecular biological experiments. Results Here, we found that copy number amplification of OPA1 and MFN1 were co-occurring and synergistically activated in tumor epithelial cells in lung cancer tissues. Both of OPA1 and MFN1 were highly expressed in LUAD tumor tissues and OPA1 high expression was associated with poor prognosis. In terms of mechanism, the damaged mitochondria activated the apoptotic signaling pathways, inducing cell cycle arrest and cell apoptosis. More interestingly, OPA1 deficiency damaged mitochondrial dynamics and further blocked the respiratory function to increase the sensitivity of tumor epithelial to CD8+ T cells in non-small cell lung cancer. Conclusions Our study demonstrated the high co-occurrence of copy number amplification and co-expression of OPA1 and MFN1 in LUAD tissue, and further revealed the contribution of OPA1 in maintaining the mitochondria respiratory function and the ability of immune evasion to CD8+ T cells of LUAD.

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“…It converts glucose to glucose-6-phosphate (G-6-P). HK2 is an isoform of HK, and in human glioblastoma cells, elevated glucose levels induce the mitochondrial separation of HK2, which then phosphorylates IκBα, and causes its destruction, thereby transcriptionally enhancing PD-L1, which promotes tumor cell immune evasion and brain tumor development ( Guo et al, 2022 ). It is reported that HK2 deficiency significantly inhibits glycolysis and tumor cell growth in HCC ( Wu et al, 2019 ), while HK2 activity suppression promotes cell death in glioblastoma ( Uludağ et al, 2022 ).…”

Section: Glycolysis-targeted Cancer Therapymentioning

confidence: 99%

The significance of glycolysis in tumor progression and its relationship with the tumor microenvironment

Zhou

Duan

et al. 2022

Front. Pharmacol.

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It is well known that tumor cells rely mainly on aerobic glycolysis for energy production even in the presence of oxygen, and glycolysis is a known modulator of tumorigenesis and tumor development. The tumor microenvironment (TME) is composed of tumor cells, various immune cells, cytokines, and extracellular matrix, among other factors, and is a complex niche supporting the survival and development of tumor cells and through which they interact and co-evolve with other tumor cells. In recent years, there has been a renewed interest in glycolysis and the TME. Many studies have found that glycolysis promotes tumor growth, metastasis, and chemoresistance, as well as inhibiting the apoptosis of tumor cells. In addition, lactic acid, a metabolite of glycolysis, can also accumulate in the TME, leading to reduced extracellular pH and immunosuppression, and affecting the TME. This review discusses the significance of glycolysis in tumor development, its association with the TME, and potential glycolysis-targeted therapies, to provide new ideas for the clinical treatment of tumors.

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Aerobic glycolysis promotes tumor immune evasion by hexokinase2-mediated phosphorylation of IκBα

Cited by 146 publications

References 44 publications

The regulation of cell homeostasis and antiviral innate immunity by autophagy during classical swine fever virus infection

The regulation of cell homeostasis and antiviral innate immunity by autophagy during classical swine fever virus infection

OPA1 supports mitochondrial dynamics and immune evasion to CD8⁺ T cell in lung adenocarcinoma

The significance of glycolysis in tumor progression and its relationship with the tumor microenvironment

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Aerobic glycolysis promotes tumor immune evasion by hexokinase2-mediated phosphorylation of IκBα

Cited by 146 publications

References 44 publications

The regulation of cell homeostasis and antiviral innate immunity by autophagy during classical swine fever virus infection

The regulation of cell homeostasis and antiviral innate immunity by autophagy during classical swine fever virus infection

OPA1 supports mitochondrial dynamics and immune evasion to CD8+ T cell in lung adenocarcinoma

The significance of glycolysis in tumor progression and its relationship with the tumor microenvironment

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OPA1 supports mitochondrial dynamics and immune evasion to CD8⁺ T cell in lung adenocarcinoma