Ginsenoside Compound K Regulates HIF-1α-Mediated Glycolysis Through Bclaf1 to Inhibit the Proliferation of Human Liver Cancer Cells.
Ginsenoside Compound K Regulates HIF-1α-Mediated Glycolysis Through Bclaf1 to Inhibit the Proliferation of Human Liver Cancer Cells.
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人参皂苷化合物 K 通过 Bclaf1 调节 HIF-1α 介导的糖酵解抑制人肝癌细胞的增殖
DOI：
10.3389/fphar.2020.583334
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发表时间：
2020
影响因子：
5.6
通讯作者：
Zhang X
中科院分区：
文献类型：
--
作者：
Zhang S;Zhang M;Chen J;Zhao J;Su J;Zhang X
本研究旨在证明化合物K（20（S）-BclaCK; CK）下调Bcl-2相关转录因子1（Bclaf 1），从而抑制缺氧诱导因子-1 α（HIF-1α）介导的糖酵解途径，抑制肝癌细胞增殖。用不同浓度的CK处理缺氧条件下的肝癌细胞（Bel-7404和Huh 7），结果显示CK对肝癌细胞的增殖有时间和浓度依赖性的抑制作用，细胞集落形成能力降低，细胞生长阻滞于G 0/G1期。CK通过调节HIF-1α及其相关泛素化蛋白的表达，促进肝癌细胞中HIF-1α泛素化的降解，并降低参与糖酵解的关键酶活性、细胞糖酵解压力和实时ATP生成速率，从而抑制糖酵解途径。同时，它还能降低缺氧肝癌细胞中Bclaf 1的表达，从而降低Bclaf 1与HIF-1α结合的能力。在低氧条件下，CK处理Bel-7404和Bclaf 1基因CRISPR/Cas9工程敲除的Huh 7细胞进一步抑制了HIF-1α的表达，促进了HIF-1α泛素化，并抑制了糖酵解途径。在二乙基亚硝胺诱导的原发性肝癌大鼠模型中，正电子发射断层扫描和计算机断层扫描显示，给予CK后，肿瘤组织体积缩小，葡萄糖摄取能力下降。Bclaf 1和HIF-1α表达增加，促进HIF-1α泛素化，抑制糖酵解途径，从而抑制肝癌细胞增殖。综上所述，本研究通过体内外实验证实了CK在缺氧肝癌细胞中下调Bclaf 1的表达，抑制HIF-1α介导的糖酵解途径，抑制细胞增殖，提示CK介导的Bclaf 1作用可能代表了肝癌患者治疗的新途径。
This study aimed to demonstrate that ginsenoside compound K (20 (S)-ginsenoside CK; CK) downregulates Bcl-2-associated transcription factor 1 (Bclaf1), which inhibits the hypoxia-inducible factor-1α (HIF-1α)-mediated glycolysis pathway to inhibit the proliferation of liver cancer cells. Treatment of hepatoma cells (Bel-7404 and Huh7) under hypoxic conditions with different concentrations of CK showed that CK inhibited the proliferation of hepatoma cells in a time- and concentration-dependent manner; furthermore, the ability of the cells to form colonies was reduced, and cell growth was blocked in the G0/G1 phase. CK promoted the degradation of HIF-1α ubiquitination in liver cancer cells by regulating the expression of HIF-1α and related ubiquitination proteins; moreover, it reduced the activity of key enzymes involved in glycolysis, the pressure of cellular glycolysis, and the rate of real-time ATP production, thereby inhibiting the glycolysis pathway. It also decreased the expression of Bclaf1 in hypoxic liver cancer cells and thus reduced the ability of Bclaf1 to bind to HIF-1α. CK treatment of Bel-7404 and Huh7 cells with CRISPR/Cas9-engineered knock out of Bclaf1 gene under hypoxic conditions further suppressed the expression of HIF-1α, promoted HIF-1α ubiquitination, and inhibited the glycolysis pathway. In a rat model of primary liver cancer induced by diethylnitrosamine, positron emission tomography and computed tomography scans showed that after CK administration, tumor tissue volumes were reduced and glucose uptake capacity decreased. Increased Bclaf1 and HIF-1α expression promoted the ubiquitination of HIF-1α and inhibited the glycolysis pathway, thereby inhibiting the proliferation of liver cancer cells. In summary, this study confirmed by in vitro and in vivo experiments that in hypoxic liver cancer cells CK downregulates the expression of Bclaf1, inhibits the HIF-1α-mediated glycolysis pathway, and inhibits cell proliferation, suggesting that the CK-mediated effects on Bclaf1 may represent a novel therapeutic approach for the treatment of liver cancer patients.
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影响因子：
3.2
作者：
Bhayani, Neil H.;Jiang, Yixing;Gusani, Niraj J.
通讯作者：
Gusani, Niraj J.
影响因子：
8.2
作者：
Shi, Jing;Xue, Wei;Li, Ke-xin
通讯作者：
Li, Ke-xin
Bclaf1 是 DNA 损伤诱导的衰老中重要的 NF-κB 信号转导器和 C/EBPβ 调节因子
影响因子：
12.4
作者：
Shao, A-w;Sun, H.;Tang, J.
通讯作者：
Tang, J.
影响因子：
--
作者：
Rigiracciolo DC;Scarpelli A;Lappano R;Pisano A;Santolla MF;De Marco P;Cirillo F;Cappello AR;Dolce V;Belfiore A;Maggiolini M;De Francesco EM
通讯作者：
De Francesco EM
影响因子：
6.7
作者：
Lee, HU;Bae, EA;Kim, DH
通讯作者：
Kim, DH