Dataset Information

Genistein suppresses aerobic glycolysis and induces hepatocellular carcinoma cell death.

ABSTRACT:

Background

Genistein is a natural isoflavone with many health benefits, including antitumour effects. Increased hypoxia-inducible factor 1 ? (HIF-1?) levels and glycolysis in tumour cells are associated with an increased risk of mortality, cancer progression, and resistance to therapy. However, the effect of genistein on HIF-1? and glycolysis in hepatocellular carcinoma (HCC) is still unclear.

Methods

Cell viability, apoptosis rate, lactate production, and glucose uptake were measured in HCC cell lines with genistein incubation. Lentivirus-expressed glucose transporter 1 (GLUT1) or/and hexokinase 2 (HK2) and siRNA of HIF-1? were used to test the direct target of genistein. Subcutaneous xenograft mouse models were used to measure in vivo efficacy of genistein and its combination with sorafenib.

Results

Genistein inhibited aerobic glycolysis and induced mitochondrial apoptosis in HCC cells. Neither inhibitors nor overexpression of HK2 or GLUTs enhance or alleviate this effect. Although stabiliser of HIF-1? reversed the effect of genistein, genistein no longer has effects on HIF-1? siRNA knockdown HCC cells. In addition, genistein enhanced the antitumour effect of sorafenib in sorafenib-resistant HCC cells and HCC-bearing mice.

Conclusions

Genistein sensitised aerobic glycolytic HCC cells to apoptosis by directly downregulating HIF-1?, therefore inactivating GLUT1 and HK2 to suppress aerobic glycolysis. The inhibitory effect of genistein on tumour cell growth and glycolysis may help identify effective treatments for HCC patients at advanced stages.

SUBMITTER: Li S

PROVIDER: S-EPMC5680469 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Publications

Genistein suppresses aerobic glycolysis and induces hepatocellular carcinoma cell death.

Li Sainan S Li Jingjing J Dai Weiqi W Zhang Qinghui Q Feng Jiao J Wu Liwei L Liu Tong T Yu Qiang Q Xu Shizan S Wang Wenwen W Lu Xiya X Chen Kan K Xia Yujing Y Lu Jie J Zhou Yingqun Y Fan Xiaoming X Mo Wenhui W Xu Ling L Guo Chuanyong C

British journal of cancer 20170919 10

<h4>Background</h4>Genistein is a natural isoflavone with many health benefits, including antitumour effects. Increased hypoxia-inducible factor 1 α (HIF-1α) levels and glycolysis in tumour cells are associated with an increased risk of mortality, cancer progression, and resistance to therapy. However, the effect of genistein on HIF-1α and glycolysis in hepatocellular carcinoma (HCC) is still unclear.<h4>Methods</h4>Cell viability, apoptosis rate, lactate production, and glucose uptake were meas ...[more]

PMID: 28926527

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Project description:BackgroundThe shortening of 3' untranslated regions (3'UTRs) of messenger RNAs(mRNAs) by alternative polyadenylation (APA) is an important mechanism for oncogene activation. Cleavage stimulation factor 2 (CSTF2), an important regulator of APA, has been reported to have a tumorigenic function in urothelial carcinoma of the bladder and lung cancers. However, the tumor-promoting role of CSTF2 in hepatocellular carcinoma (HCC) and its underlying molecular mechanism remains unclear.MethodsMultiple databases were used to analyze the expression level and prognostic value of CSTF2 in HCC. Function enrichment analysis was used to investigate the molecular mechanism of CSTF2 for the occurrence and development of HCC. The biological function in HCC cell lines in vitro was determined by CCK8, colony formation, Transwell migration, and invasion assay. Moreover, the tumorigenic function of CSTF2 in vivo was measured by a subcutaneous tumor formation or injecting four plasmids into a mouse tail vein within 5-7 s in an immunocompetent HCC mouse model. In addition, aerobic glycolysis in HCC cells was determined by measuring the extracellular acid rate (ECAR) and extracellular glucose and lactate levels.ResultsBioinformatics analysis revealed that CSTF2 was overexpressed in HCC tissues. The high expression of CSTF2 was correlated with a poor prognosis and high histological grades. CSTF2 knockout inhibited the proliferation, migration, and invasion of HCC cells. In addition, CSTF2 knockout HCC cells failed to form tumors by a subcutaneous graft experiment. Furthermore, endogenous CSTF2 knockout attenuated hepatocarcinogenesis in an immunocompetent HCC mouse model. Function enrichment analysis suggested that the high expression of CSTF2 was associated with enhanced glycolysis. Moreover, we found that CSTF2 knockout reduced the level of the short 3' UTR isoform of hexokinase 2 and increased its level of long 3'UTR. Furthermore, CSTF2 knockout inhibited ECAR levels, glucose uptake, and lactate production.ConclusionOur results indicated that CSTF2 is highly expressed in HCC and is correlated with a poor prognosis and high histological grade. The knockout of CSTF2 inhibits the tumorigenesis and procession of HCC both in vitro and in vivo. Moreover, CSTF2 is associated with enhanced glycolysis. Therefore, this study suggests that CSTF2 might be a new prognostic biomarker and therapeutic target for HCC.

Dataset Information

Genistein suppresses aerobic glycolysis and induces hepatocellular carcinoma cell death.

Background

Methods

Results

Conclusions

Publications

Genistein suppresses aerobic glycolysis and induces hepatocellular carcinoma cell death.

Similar Datasets

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