Hexokinase 1 blocks apoptotic signals at the mitochondria

Schindler, Anja; Foley, Edan

doi:10.1016/j.cellsig.2013.08.035

Cited by 60 publications

(50 citation statements)

References 37 publications

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“…1f). A previous study indicates that HK1 is partially localized in mitochondria where it functions to block apoptotic signals10. This prompted us to further explore whether a part of c-Src and HK1 also show mitochondrial location.…”

Section: Resultsmentioning

confidence: 91%

c-Src phosphorylation and activation of hexokinase promotes tumorigenesis and metastasis

et al. 2017

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It is well known that c-Src has important roles in tumorigenesis. However, it remains unclear whether c-Src contributes to metabolic reprogramming. Here we find that c-Src can interact with and phosphorylate hexokinases HK1 and HK2, the rate-limiting enzymes in glycolysis. Tyrosine phosphorylation dramatically increases their catalytic activity and thus enhances glycolysis. Mechanistically, c-Src phosphorylation of HK1 at Tyr732 robustly decreases its Km and increases its Vmax by disrupting its dimer formation. Mutation in c-Src phosphorylation site of either HK1 or HK2 remarkably abrogates the stimulating effects of c-Src on glycolysis, cell proliferation, migration, invasion, tumorigenesis and metastasis. Due to its lower Km for glucose, HK1 rather than HK2 is required for tumour cell survival when glucose is scarce. Importantly, HK1-Y732 phosphorylation level remarkably correlates with the incidence and metastasis of various clinical cancers and may serve as a marker to predict metastasis risk of primary cancers.

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Section: Resultsmentioning

confidence: 91%

c-Src phosphorylation and activation of hexokinase promotes tumorigenesis and metastasis

et al. 2017

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“…Certain glycolytic enzymes are completely localized to the mitochondria and include hexokinase I, hexokinase II, and hexokinase IV [32, 33]. Previous research has documented that many of these glycolytic enzymes have a dynamic association with the outer mitochondrial membrane, are functional, and act to increase substrate for the ETC generated by glycolysis [8, 34].…”

Section: Discussionmentioning

confidence: 99%

Proteomic analysis of the mitochondria from embryonic and postnatal rat brains reveals response to developmental changes in energy demands

Villeneuve

Stauch

Fox

2014

Journal of Proteomics

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Many biological processes converge on the mitochondria. In such systems, where many pathways converge, manipulation of the components can produce varied and far-reaching effects. Due to the centrality of the mitochondria in many cellular pathways, we decided to investigate the brain mitochondrial proteome during early development. Using a SWATH mass spectrometry-based technique, we were able to identify vast proteomic alterations between whole brain mitochondria from rats at embryonic day 18 compared to postnatal day 7. These findings include statistically significant alterations in proteins involved in glycolysis and mitochondrial trafficking/dynamics. Additionally, bioinformatic analysis enabled the identification of HIF1A and XBP1 as upstream transcriptional regulators of many of the differentially expressed proteins. These data suggest that the cell is rearranging mitochondria to accommodate special energy demands and that cytosolic proteins exert mitochondrial effects through dynamic interactions with mitochondria.

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“…Hexokinase is upregulated and activated in many cancers and translocates to mitochondria, where it inhibits mitochondria-mediated apoptosis [32]. Many events, such as oncogenic activation (c-myc, Akt), tumor suppressor mutations [p53/ Phosphatase and tensin homolog (PTEN)], and hypoxic conditions have been reported to modulate several key glycolytic factors (e.g., hexokinase activation), which confer resistance to cancer cells [33].…”

Section: Glycolytic Pathway and Apoptosis Resistance In Cancermentioning

confidence: 99%

Restoration of mitochondria function as a target for cancer therapy

Bhat

Kumar

Chaudhary

et al. 2015

Drug Discovery Today

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Defective oxidative phosphorylation has a crucial role in the attenuation of mitochondrial function, which confers therapy resistance in cancer. Various factors, including endogenous heat shock proteins (HSPs) and exogenous agents such as dichloroacetate, restore respiratory and other physiological functions of mitochondria in cancer cells. Functional mitochondria might ultimately lead to the restoration of apoptosis in cancer cells that are refractory to current anticancer agents. Here, we summarize the key reasons contributing to mitochondria dysfunction in cancer cells and whether and/or how restoration of mitochondrial function could be exploited for cancer therapeutics.

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Hexokinase 1 blocks apoptotic signals at the mitochondria

Cited by 60 publications

References 37 publications

c-Src phosphorylation and activation of hexokinase promotes tumorigenesis and metastasis

c-Src phosphorylation and activation of hexokinase promotes tumorigenesis and metastasis

Proteomic analysis of the mitochondria from embryonic and postnatal rat brains reveals response to developmental changes in energy demands

Restoration of mitochondria function as a target for cancer therapy

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