Loss of alanine-glyoxylate and serine-pyruvate aminotransferase expression accelerated the progression of hepatocellular carcinoma and predicted poor prognosis

Sun, Yufeng; Li, Wenchao; Shen, Suhung; Yang, Xuejing; Lu, Bing; Zhang, Xiaojing; Lü, Peng; Shen, Yi; Ji, Juling

doi:10.1186/s12967-019-02138-5

Cited by 16 publications

(9 citation statements)

References 72 publications

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“…The same reaction has been reported to take place in peroxisomes (Poore et al, 1997). On the other hand, loss of alanine-glyoxylate aminotransferase (AGXT) expression has been reported to accelerate the progression of hepatocellular carcinoma (Sun et al, 2019). A "futile cycle" may exist between 3-PG and glycerate through 2-phosphoglyceric acid phosphatase and glycerate kinase 1 and 2; glycerate kinase 2 is also found in the mitochondria (Guo et al, 2006).…”

Section: Pathways Leading To Pyruvate Commencing From Glucose: Intermmentioning

confidence: 70%

From Glucose to Lactate and Transiting Intermediates Through Mitochondria, Bypassing Pyruvate Kinase: Considerations for Cells Exhibiting Dimeric PKM2 or Otherwise Inhibited Kinase Activity

Chinopoulos

2020

Front. Physiol.

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A metabolic hallmark of many cancers is the increase in glucose consumption coupled to excessive lactate production. Mindful that L-lactate originates only from pyruvate, the question arises as to how can this be sustained in those tissues where pyruvate kinase activity is reduced due to dimerization of PKM2 isoform or inhibited by oxidative/nitrosative stress, posttranslational modifications or mutations, all widely reported findings in the very same cells. Hereby 17 pathways connecting glucose to lactate bypassing pyruvate kinase are reviewed, some of which transit through the mitochondrial matrix. An additional 69 converging pathways leading to pyruvate and lactate, but not commencing from glucose, are also examined. The minor production of pyruvate and lactate by glutaminolysis is scrutinized separately. The present review aims to highlight the ways through which L-lactate can still be produced from pyruvate using carbon atoms originating from glucose or other substrates in cells with kinetically impaired pyruvate kinase and underscore the importance of mitochondria in cancer metabolism irrespective of oxidative phosphorylation.

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Section: Pathways Leading To Pyruvate Commencing From Glucose: Intermmentioning

confidence: 70%

From Glucose to Lactate and Transiting Intermediates Through Mitochondria, Bypassing Pyruvate Kinase: Considerations for Cells Exhibiting Dimeric PKM2 or Otherwise Inhibited Kinase Activity

Chinopoulos

2020

Front. Physiol.

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“…In Huh7- GCK + /HK2 − cells, increased levels of alanine-glyoxylate and serine-pyruvate aminotransferase ( AGXT ) could account for this phenotype as it converts alanine and glyoxylate into pyruvate and glycine, which is also increased. Interestingly, high level of AGXT is a good prognostic marker for HCC 41 . Consistently, it was found that oxalate inhibits liver PC, resulting in reduced gluconeogenesis and lipogenesis 42 , 43 .…”

Section: Discussionmentioning

confidence: 97%

A hexokinase isoenzyme switch in human liver cancer cells promotes lipogenesis and enhances innate immunity

et al. 2021

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During the cancerous transformation of normal hepatocytes into hepatocellular carcinoma (HCC), the enzyme catalyzing the first rate-limiting step of glycolysis, namely the glucokinase (GCK), is replaced by the higher affinity isoenzyme, hexokinase 2 (HK2). Here, we show that in HCC tumors the highest expression level of HK2 is inversely correlated to GCK expression, and is associated to poor prognosis for patient survival. To further explore functional consequences of the GCK-to-HK2 isoenzyme switch occurring during carcinogenesis, HK2 was knocked-out in the HCC cell line Huh7 and replaced by GCK, to generate the Huh7-GCK+/HK2− cell line. HK2 knockdown and GCK expression rewired central carbon metabolism, stimulated mitochondrial respiration and restored essential metabolic functions of normal hepatocytes such as lipogenesis, VLDL secretion, glycogen storage. It also reactivated innate immune responses and sensitivity to natural killer cells, showing that consequences of the HK switch extend beyond metabolic reprogramming.

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“…Other genes of note were: Adora1, Serpine1, Themis, 10 Toll-like receptor ( Tlr ) genes , Spon2 and Zcchc11 ( Data S2 and Data S3 ). Among the downregulated genes, there is an enrichment in key enzymes of amino acid ( Gnmt, and Agxt ) and cholesterol metabolism such as HMG-CoA reductase ( Hmgcr ) which is implicated in liver disease and hepatocellular carcinoma ( 38 – 41 ) ( Fig. 3D ).…”

Section: Gene Expression Changes With Aging and Caloric Restrictionmentioning

confidence: 99%

Circadian alignment of early onset caloric restriction promotes longevity in male C57BL/6J mice

Acosta-Rodríguez

Rijo‐Ferreira

Izumo

et al. 2022

Science

233

197

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Caloric restriction (CR) prolongs lifespan, yet the mechanisms by which it does so remain poorly understood. Under CR, mice self-impose chronic cycles of 2-hour-feeding and 22-hour-fasting, raising the question whether calories, fasting, or time of day are causal. We show that 30%-CR is sufficient to extend lifespan 10%; however, a daily fasting interval and circadian-alignment of feeding act together to extend lifespan 35% in male C57BL/6J mice. These effects are independent of body weight. Aging induces widespread increases in gene expression associated with inflammation and decreases in expression of genes encoding components of metabolic pathways in liver from ad lib fed mice. CR at night ameliorates these aging-related changes. Thus, circadian interventions promote longevity and provide a perspective to further explore mechanisms of aging.

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Loss of alanine-glyoxylate and serine-pyruvate aminotransferase expression accelerated the progression of hepatocellular carcinoma and predicted poor prognosis

Cited by 16 publications

References 72 publications

From Glucose to Lactate and Transiting Intermediates Through Mitochondria, Bypassing Pyruvate Kinase: Considerations for Cells Exhibiting Dimeric PKM2 or Otherwise Inhibited Kinase Activity

From Glucose to Lactate and Transiting Intermediates Through Mitochondria, Bypassing Pyruvate Kinase: Considerations for Cells Exhibiting Dimeric PKM2 or Otherwise Inhibited Kinase Activity

A hexokinase isoenzyme switch in human liver cancer cells promotes lipogenesis and enhances innate immunity

Circadian alignment of early onset caloric restriction promotes longevity in male C57BL/6J mice

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