β-elemene suppresses Warburg effect in NCI-H1650 non-small-cell lung cancer cells by regulating the miR-301a-3p/AMPKα axis

Abstract β-elemene has been evidenced to suppress the development of numerous cancers including lung cancer. Previous research has found that in A549 cells, β-elemene increased the expression of adenosine monophosphate-activated protein kinase (AMPK) α (AMPKα), which negatively regulates the Warburg effect. Bioinformatics predicted that binding sites exist between AMPKα and miR-301a-3p, an miRNA that has shown oncogenic function in many cancers. The aim of this work was to investigate the effect of β-elemene on the Warburg effect in non-small-cell lung cancer (NSCLC) cells and its mechanism. Herein, the expression of miR-301a-3p was evaluated in NSCLC cells. Then, miR-301a-3p was overexpressed or silenced by mimics or inhibitors, respectively, followed by treatment with AMPK agonists or antagonists. NSCLC cells subjected to miR-301a-3p overexpression or inhibition were further treated with β-elemene. The results demonstrated that AMPKα was targeted and negatively regulated by miR-301a-3p. AMPKα agonists attenuated the Warburg effect in NSCLC cells induced by miR-301a-3p, as evidenced by the decrease in glucose level, lactic acid level, and expression of metabolism-related enzymes (glucose transporter 1 (GLUT1), hexokinase 1 (HK1), and lactate dehydrogenase A (LDHA)). Additionally, β-elemene suppressed the expression of miR-301a-3p, enhanced that of AMPKα, and inhibited the Warburg effect in NSCLC cells. The results indicated that β-elemene attenuates the Warburg effect in NSCLC cells, possibly by mediating the miR-301a-3p/AMPKα axis.

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MicroRNA-124 suppresses proliferation and glycolysis in non–small cell lung cancer cells by targeting AKT–GLUT1/HKII

Tumor Biology ◽

10.1177/1010428317706215 ◽

2017 ◽

Vol 39 (5) ◽

pp. 101042831770621 ◽

Cited By ~ 34

Author(s):

Xiaojian Zhao ◽

Caiping Lu ◽

Weiwei Chu ◽

Bing Zhang ◽

Qiang Zhen ◽

...

Keyword(s):

Lung Cancer ◽

Cell Proliferation ◽

Energy Metabolism ◽

Small Cell Lung Cancer ◽

Cancer Cells ◽

Cell Lung Cancer ◽

Glucose Transporter ◽

Small Cell ◽

Small Cell Lung ◽

Glucose Transporter 1

Non–small cell lung cancer accounts for 85% of all types of lung cancer and is the leading cause of worldwide cancer-associated mortalities. MiR-124 is epigenetically silenced in various types of cancer and plays important roles in tumor development and progression. MiR-124 was also significantly downregulated in non–small cell lung cancer patients. Glycolysis has been considered as a feature of cancer cells; hypoxia-inducible factor 1-alpha/beta and Akt are key enzymes in the regulation of glycolysis and energy metabolism in cancer cells. However, the role of miR-124 in non–small cell lung cancer cell proliferation, glycolysis, and energy metabolism remains unknown. In this research, cell proliferation was investigated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; furthermore, glucose consumption and lactic acid production were assessed; adenosine triphosphate content and NAD+/NADH were also detected. These tests were conducted using the normal non–small cell lung cancer cell line A549, which was transfected variedly with miR-mimics, miR-124 mimics, miR-124 inhibitor, pc-DNA3.1(+)-AKT1, and pc-DNA3.1(+)-AKT2 plasmid. Here, we show that miR-124 overexpression directly decreased cell growth, glucose consumption, lactate production, and energy metabolism. MiR-124 also negatively regulates glycolysis rate–limiting enzymes, glucose transporter 1 and hexokinase II. Our results also showed that miR-124 negatively regulates AKT1 and AKT2 but no regulatory effect on hypoxia-inducible factor 1-alpha/beta. Overexpression of AKT reverses the inhibitory effect of miR-124 on cell proliferation and glycolytic metabolism in non–small cell lung cancer. AKT inhibition blocks miR-124 silencing–induced AKT1/2, glucose transporter 1, hexokinase II activation, cell proliferation, and glycolytic or energy metabolism changes. In summary, this study demonstrated that miR-124 is able to inhibit proliferation, glycolysis, and energy metabolism, potentially by targeting AKT1/2–glucose transporter 1/hexokinase II in non–small cell lung cancer cells.

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