title: Mycoepoxydiene suppresses HeLa cell growth by inhibiting glycolysis and the pentose phosphate pathway.
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.
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.|State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, Xiamen University, Xiamen, Fujian, China.|School of Basic Medicine Sciences, Hubei University of Science and Technology, Xianning, Hubei, China.
authors.forename: Kehua
authors.initials: K
authors.lastname: Jin
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.|State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, Xiamen University, Xiamen, Fujian, China.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.|State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, Xiamen University, Xiamen, Fujian, China.
authors.forename: Xihuan
authors.initials: X
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.|State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, Xiamen University, Xiamen, Fujian, China.
authors.forename: Qingyan
authors.initials: Q
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.|State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, Xiamen University, Xiamen, Fujian, China.
authors.forename: Siyang
authors.initials: S
authors.lastname: Song
authors.affiliation: School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, China.
authors.forename: Yuemao
authors.initials: Y
authors.lastname: Shen
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China. xmdeng@xmu.edu.cn.|State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, Xiamen University, Xiamen, Fujian, China. xmdeng@xmu.edu.cn.
authors.forename: Xianming
authors.initials: X
authors.lastname: Deng
mesh_terms: D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D002265:Carboxylic Ester Hydrolases / Q000187:drug effects / Q000235:genetics; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D015180:Electrophoresis, Gel, Two-Dimensional; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects* / Q000235:genetics; D006367:HeLa Cells; D006593:Hexokinase / Q000187:drug effects / Q000235:genetics; D006801:Humans; D010084:Oxidation-Reduction; D010427:Pentose Phosphate Pathway / Q000187:drug effects* / Q000235:genetics; D040901:Proteomics; D011753:Pyrones / Q000494:pharmacology*; D014305:Triose-Phosphate Isomerase / Q000187:drug effects / Q000235:genetics
chemical_list: D001952:Bridged-Ring Compounds; D011753:Pyrones; C476085:mycoepoxydiene; C000609700:HK2 protein, human; D006593:Hexokinase; D002265:Carboxylic Ester Hydrolases; C022363:6-phosphogluconolactonase; D014305:Triose-Phosphate Isomerase; D005947:Glucose
keywords: Glycolysis; Growth suppression; Mycoepoxydiene; Pentose phosphate pathway