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Mycoepoxydiene suppresses HeLa cell growth by inhibiting glycolysis and the pentose phosphate pathway

  • Applied genetics and molecular biotechnology
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Abstract

Upregulation of glycolysis and the pentose phosphate pathway (PPP) is a major characteristic of the metabolic reprogramming of cancer and provides cancer cells with energy and vital metabolites to support their rapid proliferation. Targeting glycolysis and the PPP has emerged as a promising antitumor therapeutic strategy. Marine natural products are attractive sources for anticancer therapeutics, as evidenced by the antitumor drug Yondelis. Mycoepoxydiene (MED) is a natural product isolated from a marine fungus that has shown promising inhibitory efficacy against HeLa cells in vitro. We used a proteomic approach with two-dimensional gel electrophoresis (2-DE) coupled with mass spectrometry to explore the cellular targets of MED and to unravel the molecular mechanisms underlying the antitumor activity of MED in HeLa cells. Our proteomic data showed that triosephosphate isomerase (TPI) and 6-phosphogluconolactonase (PGLS), which participate in glycolysis and the PPP, respectively, were significantly downregulated by MED treatment. Functional studies revealed that the expression levels of several other enzymes involved in glycolysis and the PPP, including hexokinase 2 (HK2), phosphofructokinase 1 (PFKM), aldolase A (ALDOA), enolase 1 (ENO1), lactate dehydrogenase A (LDHA), and glucose-6-phosphate dehydrogenase (G6PD), were also reduced in a dose-dependent manner. Moreover, the LDHA and G6PD enzymatic activities in HeLa cells were inhibited by MED, and overexpression of these downregulated enzymes rescued HeLa cells from the growth inhibition induced by MED. Our data suggest that MED suppresses HeLa cell growth by inhibiting glycolysis and the PPP, which provides a mechanistic basis for the development of new therapeutics against cervical cancer.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (Nos. 81422045, U1405223, 21272195, 81661138005, and 21402165); the China’s 1000 Young Talents Program; the Fundamental Research Funds for the Central Universities of China (Nos. 2013121032 and 20720160064); and Xiamen Southern Oceanographic Center (14GYY002NF02).

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  1. Kehua Jin

    Present address: School of Basic Medicine Sciences, Hubei University of Science and Technology, Xianning, Hubei, China

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  1. State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China

    Kehua Jin, Li Li, Xihuan Sun, Qingyan Xu, Siyang Song & Xianming Deng

  2. State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, Xiamen University, Xiamen, Fujian, China

    Kehua Jin, Li Li, Xihuan Sun, Qingyan Xu, Siyang Song & Xianming Deng

  3. School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, China

    Yuemao Shen

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Jin, K., Li, L., Sun, X. et al. Mycoepoxydiene suppresses HeLa cell growth by inhibiting glycolysis and the pentose phosphate pathway. Appl Microbiol Biotechnol 101, 4201–4213 (2017). https://doi.org/10.1007/s00253-017-8187-7

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