HK2/hexokinase-II integrates glycolysis and autophagy to confer cellular protection

Tan, Valerie; Miyamoto, Shigeki

doi:10.1080/15548627.2015.1042195

Cited by 167 publications

(136 citation statements)

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“…Moreover, glycolysis is an important way to maintain cell survival in cancers including glioma and lactate is a key product as a biomarker of malignancy [21][22][23]. And HK2 is a key enzyme during glucose metabolism in glycolysis [24]. By detecting glucose consumption, lactate production and HK2 protein level, we were the first to provide that circNFIX knockdown decreased glycolysis in glioma.…”

Section: Discussionmentioning

confidence: 98%

CircNFIX promotes progression of glioma through regulating miR-378e/RPN2 axis

Ding

You

et al. 2019

J Exp Clin Cancer Res

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Background: Circular RNA nuclear factor I X (circNFIX) has been reported to play an important role in glioma progression. However, the mechanism by which circNFIX participates in glioma progression remains poorly understood.Methods: GERIA online were used to analyze the abnormally expressed genes in glioma tissues. The expression levels of circNFIX, microRNA (miR)-378e and Ribophorin-II (RPN2) were measured by quantitative real-time polymerase chain reaction or western blot. Cell cycle distribution, apoptosis, glycolysis, migration and invasion were determined by flow cytometry, special kit and trans-well assays, respectively. The target association between miR-378e and circNFIX or RPN2 was confirmed by luciferase reporter assay, RNA immunoprecipitation and pull-down. Xenograft model was established to investigate the role of circNFIX in vivo.Results: The expression of circNFIX was enhanced in glioma tissues and cells compared with matched controls and high expression of circNFIX indicated poor outcomes of patients. Knockdown of circNFIX led to arrest of cell cycle, inhibition of glycolysis, migration and invasion and promotion of apoptosis in glioma cells. circNFIX was a sponge of miR-378e. miR-378e overexpression suppressed cell cycle process, glycolysis, migration and invasion but promoted apoptosis. miR-378e silence abated the suppressive role of circNFIX knockdown in glioma progression. RPN2 as a target of miR-378e was positively regulated via circNFIX by competitively sponging miR-378e. Silencing circNFIX decreased glioma xenograft tumor growth by regulating miR-378e/RPN2 axis. Conclusion: Knockdown of circNFIX inhibits progression of glioma in vitro and in vivo by increasing miR-378e and decreasing RPN2, providing a novel mechanism for understanding the pathogenesis of glioma.

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Section: Discussionmentioning

confidence: 98%

CircNFIX promotes progression of glioma through regulating miR-378e/RPN2 axis

Ding

You

et al. 2019

J Exp Clin Cancer Res

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“…HK2 catalyzes the phosphorylation of glucose in glycolysis, and increases glucose metabolism that is required for tumorigenesis (113, 114). The expression of HK2 was selectively upregulated by the combined loss of PTEN and p53 in prostate cancer.…”

Section: Targeting Pathways That Are Critical For Survival Of P53 Mutmentioning

confidence: 99%

Molecularly targeted therapies for p53-mutant cancers

Zhao

Tahaney

Mazumdar

et al. 2017

Cell. Mol. Life Sci.

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The tumor suppressor p53 is lost or mutated in approximately half of human cancers. Mutant p53 not only loses its anti-tumor transcriptional activity, but often acquires oncogenic functions to promote tumor proliferation, invasion, and drug resistance. Traditional strategies have been taken to directly target p53 mutants through identifying small molecular compounds to deplete mutant p53, or to restore its tumor suppressive function. Accumulating evidence suggest that cancer cells with mutated p53 often exhibit specific functional dependencies on secondary genes or pathways to survive, providing alternative targets to indirectly treat p53-mutant cancers. Targeting these genes or pathways, critical for survival in the presence of p53 mutations, holds great promise for cancer treatment. In addition, mutant p53 often exhibits novel gain-of-functions to promote tumor growth and metastasis. Here, we review and discuss strategies targeting mutant p53, with focus on targeting the mutant p53 protein directly, and on the progress of identifying genes and pathways required in p53-mutant cells.

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“…HK2, the first rate‐limiting enzyme of glycolysis, was found to control glycolysis fluxes in rat hepatocarcinoma (AS‐30D) and HeLa cells . While HK2 demonstrated to induce autophagy in response to glucose deprivation, it could also serve as a molecular switch from glycolysis to autophagy via inhibiting mammalian target of rapamycin (mTOR) . In prostate cancer cells, HK2 was found to regulate aerobic glycolysis and activate AMPK‐dependent autophagy .…”

Section: Resultsmentioning

confidence: 99%

“…[41] While HK2 demonstrated to induce autophagy in response to glucose deprivation, it could also serve as a molecular switch from glycolysis to autophagy via inhibiting mammalian target of rapamycin (mTOR). [42,43] In prostate cancer cells, HK2 was found to regulate aerobic glycolysis and activate AMPK-dependent autophagy. [44] We found that, although either RN56-6 or RN56-49 promoted autophagy, they regulated the expression of HK2 differentially.…”

Section: Rn56-6 and Rn56-49 Induce Autophagy Through Glycolytic Pathwaymentioning

confidence: 99%

Chloropupukeananin and Pestalofone C Regulate Autophagy through AMPK and Glycolytic Pathway

Guo

Zhang

Gao

et al. 2020

Chemistry & Biodiversity

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Chloropupukeananin (RN56‐6) and Pestalofone C (RN56‐49), isolated from the culture of the plant endophytic fungus Pestalotiopsis fici, have been shown cytotoxic, anti‐HIV, and antimicrobial activities. However, the underlying mechanism of their regulatory roles in autophagy remains unknown. In the present study, we revealed that both compounds increased the formation of autophagosome and enhanced autophagic flux. While RN56‐6 upregulated the expression of HK2, one of the key rate‐limiting enzymes of glycolysis, the inhibition of glycolysis chemically attenuated RN56‐6‐induced autophagy. On the contrary, RN56‐49 downregulated the expression of HK2, while the suppression of glycolysis promoted RN56‐49‐dependent autophagic flux. Moreover, the knockdown of AMPKβ1, a scaffolding subunit of AMPK, decreased autophagy induced by these two compounds. Collectively, these findings revealed that RN56‐6 and RN56‐49 regulated autophagic process through AMPK and glycolytic pathway.

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HK2/hexokinase-II integrates glycolysis and autophagy to confer cellular protection

Cited by 167 publications

References 0 publications

CircNFIX promotes progression of glioma through regulating miR-378e/RPN2 axis

CircNFIX promotes progression of glioma through regulating miR-378e/RPN2 axis

Molecularly targeted therapies for p53-mutant cancers

Chloropupukeananin and Pestalofone C Regulate Autophagy through AMPK and Glycolytic Pathway

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