Quantitative proteomics revealed energy metabolism pathway alterations in human epithelial ovarian carcinoma and their regulation by the antiparasite drug ivermectin: data interpretation in the context of 3P medicine



Energy metabolism abnormality is the hallmark in epithelial ovarian carcinoma (EOC). This study aimed to investigate energy metabolism pathway alterations and their regulation by the antiparasite drug ivermectin in EOC for the discovery of energy metabolism pathway-based molecular biomarker pattern and therapeutic targets in the context of predictive, preventive, and personalized medicine (PPPM) in EOC.


iTRAQ-based quantitative proteomics was used to identify mitochondrial differentially expressed proteins (mtDEPs) between human EOC and control mitochondrial samples isolated from 8 EOC and 11 control ovary tissues from gynecologic surgery of Chinese patients, respectively. Stable isotope labeling with amino acids in cell culture (SILAC)-based quantitative proteomics was used to analyze the protein expressions of energy metabolic pathways in EOC cells treated with and without ivermectin. Cell proliferation, cell cycle, apoptosis, and important molecules in energy metabolism pathway were examined before and after ivermectin treatment of different EOC cells.


In total, 1198 mtDEPs were identified, and various mtDEPs were related to energy metabolism changes in EOC, with an interesting result that EOC tissues had enhanced abilities in oxidative phosphorylation (OXPHOS), Kreb’s cycle, and aerobic glycolysis, for ATP generation, with experiment-confirmed upregulations of UQCRH in OXPHOS; IDH2, CS, and OGDHL in Kreb’s cycle; and PKM2 in glycolysis pathways. Importantly, PDHB that links glycolysis with Kreb’s cycle was upregulated in EOC. SILAC-based quantitative proteomics found that the protein expression levels of energy metabolic pathways were regulated by ivermectin in EOC cells. Furthermore, ivermectin demonstrated its strong abilities to inhibit proliferation and cell cycle and promote apoptosis in EOC cells, through molecular networks to target PFKP in glycolysis; IDH2 and IDH3B in Kreb’s cycle; ND2, ND5, CYTB, and UQCRH in OXPHOS; and MCT1 and MCT4 in lactate shuttle to inhibit EOC growth.


Our findings revealed that the Warburg and reverse Warburg effects coexisted in human ovarian cancer tissues, provided the first multiomics-based molecular alteration spectrum of ovarian cancer energy metabolism pathways (aerobic glycolysis, Kreb’s cycle, oxidative phosphorylation, and lactate shuttle), and demonstrated that the antiparasite drug ivermectin effectively regulated these changed molecules in energy metabolism pathways and had strong capability to inhibit cell proliferation and cell cycle progression and promote cell apoptosis in ovarian cancer cells. The observed molecular changes in energy metabolism pathways bring benefits for an in-depth understanding of the molecular mechanisms of energy metabolism heterogeneity and the discovery of effective biomarkers for individualized patient stratification and predictive/prognostic assessment and therapeutic targets/drugs for personalized therapy of ovarian cancer patients.

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one-dimensional gel electrophoresis

3P medicine:

predictive, preventive, and personalized medicine (PPPM)


ATP binding cassette subfamily B member 1


ATP-binding cassette, subfamily B (MDR/TAP), member 1B


ATP-binding cassette subfamily G member 2


cytoplasmic aconitate hydratase


alcohol dehydrogenase 5 class III chi polypeptide


AKT serine/threonine kinase 1


APC regulator of WNT signaling pathway


amyloid beta precursor protein


adenosine triphosphate


ATP synthase membrane subunit c locus 1


ATP synthase F0 subunit 6


ATPase H+ transporting V0 subunit c


ATPase H+ transporting V1 subunit D




BRCA1 DNA repair associated


BRCA2 DNA repair associated


cancer antigen 125


cancer-associated fibroblasts


Cell Counting Kit-8


chronic myeloid leukemia


acetyl-coenzyme A


cytochrome c oxidase subunit


cytochrome c oxidase copper chaperone COX17


cytochrome c oxidase subunit II


cytochrome c oxidase subunit 4I1


cytochrome c oxidase subunit 4I2


cytochrome c oxidase subunit 6C


cytochrome c oxidase subunit 7A2


cytochrome c oxidase subunit 7A2-like


citrate synthase


cytochrome P450 family 3 subfamily A member 4


mitochondrially encoded cytochrome b


dimethyl sulfoxide


deoxyribonucleic acid




eukaryotic translation initiation factor 4A3


enolase 1


epithelial ovarian carcinoma


mitogen-activated protein kinase 3


electron transport chain


fluorescence-activated cell sorting


2,4-dienoyl-CoA reductase


Food and Drug Administration


fumarate hydratase


G0/G cell cycle phase


glyceraldehyde-3-phosphate dehydrogenase


glycine receptor beta


golgin A2


Gene Ontology


glucose-6-phosphate isomerase


the half maximal inhibitory concentration


isocitrate dehydrogenase (NADP(+)) 2


isocitrate dehydrogenase [NAD] subunit alpha, mitochondrial


isocitrate dehydrogenase (NAD(+)) 3 noncatalytic subunit beta


Ingenuity Pathway Analysis


isobaric tags for relative and absolute quantitation




Kyoto Encyclopedia of Genes and Genomes


karyopherin subunit beta 1

Kreb’s cycle:

tricarboxylic acid cycle


liquid chromatography-tandem mass spectrometry


lactate dehydrogenase A


lactate dehydrogenase B


long noncoding RNAs


mitogen-activated protein kinase 1


mitogen-activated protein kinase 13


mitogen-activated protein kinase 3


solute carrier family 16 member 1


solute carrier family 16 member 4


monocarboxylate transporters


malate dehydrogenase 2



M r :

protein molecular weight


messenger RNA


multidrug resistance-associated protein 1


mitochondrial ribosomal protein L41


mitochondrial ribosomal protein L41


mitochondrial ribosomal protein L49


mitochondrial ribosomal protein L51


mitochondrial ribosomal protein L52


mitochondrial ribosomal protein L53


mitochondrial ribosomal protein L54


mitochondrial ribosomal protein L55


mitochondrial ribosomal protein S10


mitochondrial ribosomal protein S12


mitochondrial ribosomal protein S15


mitochondrial ribosomal protein S17


mitochondrial ribosomal protein S21


mitochondrial ribosomal protein S23


mitochondrial ribosomal protein S33


mitochondrial ribosomal protein S6


mitochondrial ribosomal protein S9


mitochondrial differentially expressed proteins


mechanistic target of rapamycin kinase


mitochondrially encoded NADH dehydrogenase 1


mitochondrially encoded NADH dehydrogenase 2


mitochondrially encoded NADH dehydrogenase 5


NFKB inhibitor alpha


oxoglutarate dehydrogenase L


oxidative phosphorylation


cyclin-dependent kinase inhibitor 1A


cyclin-dependent kinase inhibitor 1B


purinergic receptor P2X 4


purinergic receptor P2X 7


p21 (RAC1)-activated kinase 1


polyADP-ribose polymerase inhibitor


phosphoenolpyruvate carboxykinase [GTP], mitochondrial


pyruvate dehydrogenase complex


pyruvate dehydrogenase E1 subunit beta


phosphofructokinase, platelet

pI :

isoelectric point


pyruvate kinase muscle


pyruvate kinase M2


predictive, preventive, and personalized medicine


posttranslational modifications


mitochondrial cytochrome b-c1 complex subunit 6


quantitative real-time PCR




SURP and G-patch domain containing 1


ribonucleic acid


reactive oxygen species


strong cation exchange chromatography


standard deviation




stable isotope labeling with amino acids in cell culture


small nucleolar RNA host gene 3


signal transducer and activator of transcription 3


succinate–CoA ligase GDP-forming subunit beta


tumor necrosis factor


translocase of outer mitochondrial membrane 20


ubiquinol-cytochrome c reductase hinge protein


voltage-dependent anion channel 1


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The authors acknowledge the financial support from the Shandong First Medical University Talent Introduction Funds (to X.Z.) and the Hunan Provincial Hundred Talent Plan (to X.Z.).

Author information




N.L. carried out the cell experiments, analyzed the data, prepared the figures and tables, and wrote the manuscript. H.L. collected the samples, prepared the mitochondrial samples, and participated in data analysis and table preparation. Y.W. participated in western blot experiments. L.C. collected tumor tissue samples and performed clinical diagnosis. X.Z. conceived the concept, designed the experiments and manuscript, instructed experiments and data analysis, coordinated and obtained the mitochondrial iTRAQ quantitative proteomic data, supervised the results, wrote and critically revised the manuscript, and was responsible for its financial support and the corresponding works. All authors approved the final manuscript.

Corresponding author

Correspondence to Xianquan Zhan.

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The authors declare that they have no competing interests.

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Not applicable

Ethical approval

All the patients were informed about the purposes of the study and, consequently, have signed their “consent of the patient.” All investigations conformed to the principles outlined in the Declaration of Helsinki and were performed with permission by the responsible Medical Ethics Committee of Xiangya Hospital, Central South University, China.

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Abbreviations for all particular genes and proteins can be found at the following link: https://www.ncbi.nlm.nih.gov/gene/.

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Li, N., Li, H., Wang, Y. et al. Quantitative proteomics revealed energy metabolism pathway alterations in human epithelial ovarian carcinoma and their regulation by the antiparasite drug ivermectin: data interpretation in the context of 3P medicine. EPMA Journal (2020). https://doi.org/10.1007/s13167-020-00224-z

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  • Epithelial ovarian carcinoma
  • Ivermectin
  • Mitochondrial proteomics
  • Warburg effect
  • Reverse Warburg effect
  • iTRAQ-based quantitative proteomics
  • SILAC-based quantitative proteomics
  • Energy metabolism pathway
  • Aerobic glycolysis
  • Kreb’s cycle
  • Oxidative phosphorylation
  • Lactate shuttle
  • Molecular biomarker pattern
  • Early diagnosis
  • Prognostic assessment
  • Predictive preventive personalized medicine (PPPM)