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Aspirin inhibits the proliferation of hepatoma cells through controlling GLUT1-mediated glucose metabolism

Acta Pharmacologica Sinicavolume 40pages122132 (2019) | Download Citation

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Abstract

Aspirin can efficiently inhibit liver cancer growth, but the mechanism is poorly understood. In this study, we report that aspirin modulates glucose uptake through downregulating glucose transporter 1 (GLUT1), leading to the inhibition of hepatoma cell proliferation. Our data showed that aspirin significantly decreased the levels of reactive oxygen species (ROS) and glucose consumption in hepatoma cells. Interestingly, we identified that GLUT1 and HIF1α could be decreased by aspirin. Mechanically, we demonstrated that the -1008/-780 region was the regulatory element of transcriptional factor NF-κB in GLUT1 promoter by luciferase report gene assays. PDTC, an inhibitor of NF-κB, could suppress the expression of GLUT1 in HepG2 and H7402 cells, followed by affecting the levels of ROS and glucose consumption. CoCl2-activated HIF1α expression could slightly rescue the GLUT1 expression inhibited by aspirin or PDTC, suggesting that aspirin depressed GLUT1 through targeting NF-κB or NF-κB/HIF1α signaling. Moreover, we found that GLUT1 was highly expressed in clinical HCC tissues relating to their paired adjacent normal tissues. Importantly, we observed that high level of GLUT1 was significantly correlated with the poor relapse-free survival of HCC patients by analysis of public data. Functionally, overexpression of GLUT1 blocked the PDTC-induced or aspirin-induced inhibition of glucose metabolism in HepG2 cells. Conversely, aspirin failed to work when GLUT1 was stably knocked down in the cells. Administration of aspirin could depress the growth of hepatoma cells through controlling GLUT1 in vitro and in vivo. Thus, our finding provides new insights into the mechanism by which aspirin depresses liver cancer.

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Acknowledgements

This work was supported in part by National Basic Research Program of China (973 Program, No. 2015CB553703) and National Natural Science Foundation of China (No. 31670769, No. 31470756).

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Author notes

  1. These authors contributed equally: Yun-xia Liu and Jin-yan Feng.

Affiliations

  1. Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin, 300071, China

    • Yun-xia Liu
    • , Jin-yan Feng
    • , Ming-ming Sun
    • , Guang Yang
    • , Ya-nan Bu
    • , Man Zhao
    • , Wei-ying Zhang
    • , Hong-feng Yuan
    •  & Xiao-dong Zhang
  2. Department of Biochemistry, College of Life Sciences, Nankai University, Tianjin, 300071, China

    • Bo-wen Liu
    •  & Tian-jiao Wang

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Contributions

XZ conceived the projects, designed the experiments, and drafted the manuscript. YL and JF designed the experiments and drafted the manuscript. YL, JF, MS, BL, GY, YB, MZ, and TW performed the experiments. MS and WZ analyzed the experiments shown in all of the figures. HY provided technical assistance. All authors reviewed the results and approved the final version of the manuscript.

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The authors declare that they have no conflict of interest.

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Correspondence to Xiao-dong Zhang.

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https://doi.org/10.1038/s41401-018-0014-x