Abstract:
AIMS:Enhanced aerobic glycolysis is an essential hallmark of malignant cancer. Blocking the glycolytic pathway has been suggested as a therapeutic strategy to impair the proliferation of tumor cells. Metformin, a widely used anti-diabetes drug, exhibits anti-tumor properties. However, the underlying molecular mechanism of its action linking glucose metabolism with the suppression of proliferation has not been fully clarified. MAIN METHODS:Stable isotope tracing technology and gas chromatography-mass spectrometry method were utilized to analyze the effect of metformin on glycolytic flux in HCC cells. Western blot and immunohistochemistry were utilized to analyze the expression of phosphofructokinase-1 (PFK1) and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) in HCC cells or xenograft tumor tissues. Lactate measurement and glucose uptake assay were used to analyze the level of lactate and glucose in the presence of frucose-2,6-diphosphate (F2,6BP) in HCC cells treated with metformin. KEY FINDINGS:We found that metformin significantly impaired hepatoma cell proliferation by inhibiting the glycolytic flux via PFK1 blockade. Interestingly, activation of PFK1 by F2,6BP reverses the inhibitory effect of metformin on hepatoma cell proliferation and glycolysis. Mechanistically, PFKFB3,a potent allosteric activator of PFK1, was markedly suppressed through inhibiting hypoxia-induced factor 1 (HIF-1α) accumulation mediated by metformin. SIGNIFICANCE:Taken together these data indicate that HIF-1α/PFKFB3/PFK1 regulatory axis is a vital determinant of glucose metabolic reprogramming in hepatocellular carcinoma, which gives new insights into the action of metformin in combatting liver cancer.
journal_name
Life Scijournal_title
Life sciencesauthors
Hu,Zeng Z,Xia Q,Liu Z,Feng X,Chen J,Huang M,Chen L,Fang Z,Liu Q,Zeng H,Zhou X,Liu Jdoi
10.1016/j.lfs.2019.116966subject
Has Abstractpub_date
2019-12-15 00:00:00pages
116966eissn
0024-3205issn
1879-0631pii
S0024-3205(19)30893-8journal_volume
239pub_type
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