Mycoepoxydiene suppresses HeLa cell growth by inhibiting glycolysis and the pentose phosphate pathway
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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.
KeywordsMycoepoxydiene Growth suppression Glycolysis Pentose phosphate pathway
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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Conflict of interest
The authors have no conflict of interest to declare.
This article does not contain any studies with human participants or animals performed by any of the authors.
- Abbate F, Casini A, Owa T, Scozzafava A, Supuran CT (2004) Carbonic anhydrase inhibitors: E7070, a sulfonamide anticancer agent, potently inhibits cytosolic isozymes I and II, and transmembrane, tumor-associated isozyme IX. Bioorg Med Chem Lett 14:217–223. doi: 10.1016/j.bmcl.2003.09.062 CrossRefPubMedGoogle Scholar
- Chen M, Huang SL, Zhang XQ, Zhang B, Zhu H, Yang VW, Zou XP (2012a) Reversal effects of pantoprazole on multidrug resistance in human gastric adenocarcinoma cells by down-regulating the V-ATPases/mTOR/HIF-1α/P-gp and MRP1 signaling pathway in vitro and in vivo. J Cell Biochem 113:2474–2487. doi: 10.1002/jcb.24122 CrossRefPubMedPubMedCentralGoogle Scholar
- Chiche J, Ilc K, Laferriere J, Trottier E, Dayan F, Mazure NM, Brahimi-Horn MC, Pouyssegur J (2009) Hypoxia-inducible carbonic anhydrase IX and XII promote tumor cell growth by counteracting acidosis through the regulation of the intracellular pH. Cancer Res 69:358–368. doi: 10.1158/0008-5472.CAN-08-2470 CrossRefPubMedGoogle Scholar
- Clem B, Telang S, Clem A, Yalcin A, Meier J, Simmons A, Rasku MA, Arumugam S, Dean WL, Eaton J, Lane A, Trent JO, Chesney J (2008) Small-molecule inhibition of 6-phosphofructo-2-kinase activity suppresses glycolytic flux and tumor growth. Mol Cancer Ther 7:110–120. doi: 10.1158/1535-7163.MCT-07-0482 CrossRefPubMedGoogle Scholar
- Fan J, Hitosugi T, Chung TW, Xie J, Ge Q, Gu TL, Polakiewicz RD, Chen GZ, Boggon TJ, Lonial S, Khuri FR, Kang S, Chen J (2011) Tyrosine phosphorylation of lactate dehydrogenase A is important for NADH/NAD(+) redox homeostasis in cancer cells. Mol Cell Biol 31:4938–4950. doi: 10.1128/MCB.06120-11 CrossRefPubMedPubMedCentralGoogle Scholar
- Giammarioli AM, Gambardella L, Barbati C, Pietraforte D, Tinari A, Alberton M, Gnessi L, Griffin RJ, Minetti M, Malorni W (2012) Differential effects of the glycolysis inhibitor 2-deoxy-D-glucose on the activity of pro-apoptotic agents in metastatic melanoma cells, and induction of a cytoprotective autophagic response. Int J Cancer 131:E337–E347. doi: 10.1002/ijc.26420 CrossRefPubMedGoogle Scholar
- Hinton A, Sennoune SR, Bond S, Fang M, Reuveni M, Sahagian GG, Jay D, Martinez-Zaguilan R, Forgac M (2009) Function of a subunit isoforms of the V-ATPase in pH homeostasis and in vitro invasion of MDA-MB231 human breast cancer cells. J Biol Chem 284:16400–16408. doi: 10.1074/jbc.M901201200 CrossRefPubMedPubMedCentralGoogle Scholar
- Le A, Cooper CR, Gouw AM, Dinavahi R, Maitra A, Deck LM, Royer RE, Vander Jagt DL, Semenza GL, Dang CV (2010) Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proc Natl Acad Sci U S A 107:2037–2042. doi: 10.1073/pnas.0914433107 CrossRefPubMedPubMedCentralGoogle Scholar
- Li L, Fath MA, Scarbrough PM, Watson WH, Spitz DR (2015) Combined inhibition of glycolysis, the pentose cycle, and thioredoxin metabolism selectively increases cytotoxicity and oxidative stress in human breast and prostate cancer. Redox Biol 4:127–135. doi: 10.1016/j.redox.2014.12.001 CrossRefPubMedGoogle Scholar
- Mo XG, Chen QW, Li XS, Zheng MM, Ke DZ, Deng W, Li GQ, Jiang J, Wu ZQ, Wang L, Wang P, Yang Y, Cao GY (2011) Suppression of NHE1 by small interfering RNA inhibits HIF-1α-induced angiogenesis in vitro via modulation of calpain activity. Microvasc Res 81:160–168. doi: 10.1016/j.mvr.2010.12.004 CrossRefPubMedGoogle Scholar
- Nilsson C, Kågedal K, Johansson U, Ollinger K (2003) Analysis of cytosolic and lysosomal pH in apoptotic cells by flow cytometry. Methods Cell Sci 25:10Google Scholar
- Palmieri D, Fitzgerald D, Shreeve SM, Hua E, Bronder JL, Weil RJ, Davis S, Stark AM, Merino MJ, Kurek R, Mehdorn HM, Davis G, Steinberg SM, Meltzer PS, Aldape K, Steeg PS (2009) Analyses of resected human brain metastases of breast cancer reveal the association between up-regulation of hexokinase 2 and poor prognosis. Mol Cancer Res 7:1438–1445. doi: 10.1158/1541-7786.MCR-09-0234 CrossRefPubMedPubMedCentralGoogle Scholar
- Raez LE, Papadopoulos K, Ricart AD, Chiorean EG, Dipaola RS, Stein MN, Rocha Lima CM, Schlesselman JJ, Tolba K, Langmuir VK, Kroll S, Jung DT, Kurtoglu M, Rosenblatt J, Lampidis TJ (2013) A phase I dose-escalation trial of 2-deoxy-D-glucose alone or combined with docetaxel in patients with advanced solid tumors. Cancer Chemother Pharmacol 71:523–530. doi: 10.1007/s00280-012-2045-1 CrossRefPubMedGoogle Scholar
- Reshkin SJ, Bellizzi A, Cardone RA, Tommasino M, Casavola V, Paradiso A (2003) Paclitaxel induces apoptosis via protein kinase A- and p38 mitogen-activated protein-dependent inhibition of the Na+/H+ exchanger (NHE) NHE isoform 1 in human breast cancer cells. Clin Cancer Res 9:2366–2373PubMedGoogle Scholar
- Somparn P, Hirankarn N, Leelahavanichkul A, Khovidhunkit W, Thongboonkerd V, Avihingsanon Y (2012) Urinary proteomics revealed prostaglandin H(2)D-isomerase, not Zn-α2-glycoprotein, as a biomarker for active lupus nephritis. J Proteome 75:3240–3247. doi: 10.1016/j.jprot.2012.03.034 CrossRefGoogle Scholar
- Stein M, Lin H, Jeyamohan C, Dvorzhinski D, Gounder M, Bray K, Eddy S, Goodin S, White E, Dipaola RS (2010) Targeting tumor metabolism with 2-deoxyglucose in patients with castrate-resistant prostate cancer and advanced malignancies. Prostate 70:1388–1394. doi: 10.1002/pros.21172 CrossRefPubMedPubMedCentralGoogle Scholar
- Su XH, Chen Q, Chen WB, Chen TH, Li WJ, Li Y, Dou XF, Zhang YF, Shen YM, Wu H, Yu CD (2014) Mycoepoxydiene inhibits activation of BV2 microglia stimulated by lipopolysaccharide through suppressing NF-kappa B, ERK 1/2 and toll-like receptor pathways. Int Immunopharmacol 19:88–93. doi: 10.1016/j.intimp.2014.01.004 CrossRefPubMedGoogle Scholar
- Vanamala J, Radhakrishnan S, Reddivari L, Bhat VB, Ptitsyn A (2011) Resveratrol suppresses human colon cancer cell proliferation and induces apoptosis via targeting the pentose phosphate and the Talin-FAK signaling pathways—a proteomic approach. Proteome Sci 9:1–11. doi: 10.1186/1477-5956-9-49 CrossRefGoogle Scholar
- Wang JF, Zhao BB, Zhang W, Wu XA, Wang RY, Huang YJ, Chen D, Park K, Weimer BC, Shen YM (2010) Mycoepoxydiene, a fungal polyketide, induces cell cycle arrest at the G2/M phase and apoptosis in HeLa cells. Bioorg Med Chem Lett 20:7054–7058. doi: 10.1016/j.bmcl.2010.09.105 CrossRefPubMedGoogle Scholar
- Wei J, Zhang Y, Luo Y, Wang Z, Bi S, Song D, Dai Y, Wang T, Qiu L, Wen L, Yuan L, Yang JY (2014) Aldose reductase regulates miR-200a-3p/141-3p to coordinate Keap1-Nrf2, Tgfbeta1/2, and Zeb1/2 signaling in renal mesangial cells and the renal cortex of diabetic mice. Free Radic Biol Med 67:91–102. doi: 10.1016/j.freeradbiomed.2013.10.811 CrossRefPubMedGoogle Scholar
- Zhang Z, Liew CW, Handy DE, Zhang Y, Leopold JA, Hu J, Guo L, Kulkarni RN, Loscalzo J, Stanton RC (2010) High glucose inhibits glucose-6-phosphate dehydrogenase, leading to increased oxidative stress and beta-cell apoptosis. FASEB J 24:1497–1505. doi: 10.1096/fj.09-136572 CrossRefPubMedPubMedCentralGoogle Scholar