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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

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Abstract

Objective

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.

Methods

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.

Results

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.

Conclusions

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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Abbreviations

1DGE:

one-dimensional gel electrophoresis

3P medicine:

predictive, preventive, and personalized medicine (PPPM)

ABCB1:

ATP binding cassette subfamily B member 1

Abcb1b:

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

ABCG2:

ATP-binding cassette subfamily G member 2

ACO1:

cytoplasmic aconitate hydratase

ADH5:

alcohol dehydrogenase 5 class III chi polypeptide

Akt:

AKT serine/threonine kinase 1

APC:

APC regulator of WNT signaling pathway

APP:

amyloid beta precursor protein

ATP:

adenosine triphosphate

ATP5G1:

ATP synthase membrane subunit c locus 1

ATP6:

ATP synthase F0 subunit 6

ATP6V0C:

ATPase H+ transporting V0 subunit c

ATP6V1D:

ATPase H+ transporting V1 subunit D

AZD2281:

olaparib

BRCA1:

BRCA1 DNA repair associated

BRCA2:

BRCA2 DNA repair associated

CA-125:

cancer antigen 125

CAFs:

cancer-associated fibroblasts

CCK8:

Cell Counting Kit-8

CML:

chronic myeloid leukemia

CoA:

acetyl-coenzyme A

COX1:

cytochrome c oxidase subunit

COX17:

cytochrome c oxidase copper chaperone COX17

COX2:

cytochrome c oxidase subunit II

COX4I1:

cytochrome c oxidase subunit 4I1

COX4I2:

cytochrome c oxidase subunit 4I2

COX6C:

cytochrome c oxidase subunit 6C

COX7A2:

cytochrome c oxidase subunit 7A2

COX7A2L:

cytochrome c oxidase subunit 7A2-like

CS:

citrate synthase

CYP3A4:

cytochrome P450 family 3 subfamily A member 4

CYTB:

mitochondrially encoded cytochrome b

DMSO:

dimethyl sulfoxide

DNA:

deoxyribonucleic acid

EdU:

5-ethynyl-2′-deoxyuridine

EIF4A3:

eukaryotic translation initiation factor 4A3

ENO1:

enolase 1

EOC:

epithelial ovarian carcinoma

ERK1/2:

mitogen-activated protein kinase 3

ETC:

electron transport chain

FACS:

fluorescence-activated cell sorting

FADH2:

2,4-dienoyl-CoA reductase

FDA:

Food and Drug Administration

FH:

fumarate hydratase

G0/G:

G0/G cell cycle phase

GAPDH:

glyceraldehyde-3-phosphate dehydrogenase

GLRB:

glycine receptor beta

GM130:

golgin A2

GO:

Gene Ontology

GPI:

glucose-6-phosphate isomerase

IC50:

the half maximal inhibitory concentration

IDH2:

isocitrate dehydrogenase (NADP(+)) 2

IDH3A:

isocitrate dehydrogenase [NAD] subunit alpha, mitochondrial

IDH3B:

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

IPA:

Ingenuity Pathway Analysis

iTRAQ:

isobaric tags for relative and absolute quantitation

K:

lysine

KEGG:

Kyoto Encyclopedia of Genes and Genomes

KPNB1:

karyopherin subunit beta 1

Kreb’s cycle:

tricarboxylic acid cycle

LC-MS/MS:

liquid chromatography-tandem mass spectrometry

LDHA:

lactate dehydrogenase A

LDHB:

lactate dehydrogenase B

lncRNA:

long noncoding RNAs

MAPK1:

mitogen-activated protein kinase 1

MAPK13:

mitogen-activated protein kinase 13

MAPK3:

mitogen-activated protein kinase 3

MCT1:

solute carrier family 16 member 1

MCT4:

solute carrier family 16 member 4

MCTs:

monocarboxylate transporters

MDH2:

malate dehydrogenase 2

miRNA:

microRNA

M r :

protein molecular weight

mRNA:

messenger RNA

MRP1:

multidrug resistance-associated protein 1

MRPL41:

mitochondrial ribosomal protein L41

MRPL46:

mitochondrial ribosomal protein L41

MRPL49:

mitochondrial ribosomal protein L49

MRPL51:

mitochondrial ribosomal protein L51

MRPL52:

mitochondrial ribosomal protein L52

MRPL53:

mitochondrial ribosomal protein L53

MRPL54:

mitochondrial ribosomal protein L54

MRPL55:

mitochondrial ribosomal protein L55

MRPS10:

mitochondrial ribosomal protein S10

MRPS12:

mitochondrial ribosomal protein S12

MRPS15:

mitochondrial ribosomal protein S15

MRPS17:

mitochondrial ribosomal protein S17

MRPS21:

mitochondrial ribosomal protein S21

MRPS23:

mitochondrial ribosomal protein S23

MRPS33:

mitochondrial ribosomal protein S33

MRPS6:

mitochondrial ribosomal protein S6

MRPS9:

mitochondrial ribosomal protein S9

mtDEPs:

mitochondrial differentially expressed proteins

mTOR:

mechanistic target of rapamycin kinase

NADH:

mitochondrially encoded NADH dehydrogenase 1

ND2:

mitochondrially encoded NADH dehydrogenase 2

ND5:

mitochondrially encoded NADH dehydrogenase 5

NFKBIA:

NFKB inhibitor alpha

OGDHL:

oxoglutarate dehydrogenase L

OXPHOS:

oxidative phosphorylation

p21:

cyclin-dependent kinase inhibitor 1A

p27:

cyclin-dependent kinase inhibitor 1B

P2RX4:

purinergic receptor P2X 4

P2RX7:

purinergic receptor P2X 7

PAK1:

p21 (RAC1)-activated kinase 1

PARP:

polyADP-ribose polymerase inhibitor

PCK2:

phosphoenolpyruvate carboxykinase [GTP], mitochondrial

PDC:

pyruvate dehydrogenase complex

PDHB:

pyruvate dehydrogenase E1 subunit beta

PFKP:

phosphofructokinase, platelet

pI :

isoelectric point

PKM:

pyruvate kinase muscle

PKM2:

pyruvate kinase M2

PPPM:

predictive, preventive, and personalized medicine

PTMs:

posttranslational modifications

QCR6:

mitochondrial cytochrome b-c1 complex subunit 6

qRT-PCR:

quantitative real-time PCR

R:

arginine

Rbp:

SURP and G-patch domain containing 1

RNA:

ribonucleic acid

ROS:

reactive oxygen species

SCX:

strong cation exchange chromatography

SD:

standard deviation

SDT:

N-hydroxysuccinimide

SILAC:

stable isotope labeling with amino acids in cell culture

SNHG3:

small nucleolar RNA host gene 3

STAT3:

signal transducer and activator of transcription 3

SUCLG2:

succinate–CoA ligase GDP-forming subunit beta

TNF:

tumor necrosis factor

TOMM20:

translocase of outer mitochondrial membrane 20

UQCRH:

ubiquinol-cytochrome c reductase hinge protein

VDAC1:

voltage-dependent anion channel 1

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Funding

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.).

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Authors and Affiliations

  1. University Creative Research Initiatives Center, Shandong First Medical University, 6699 Qingdao Road, Jinan, 250117, Shandong, People’s Republic of China

    Na Li & Xianquan Zhan

  2. Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, People’s Republic of China

    Na Li, Ya Wang & Xianquan Zhan

  3. State Local Joint Engineering Laboratory for Anticancer Drugs, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, People’s Republic of China

    Na Li, Ya Wang & Xianquan Zhan

  4. Department of Obstetrics and Gynecology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, People’s Republic of China

    Huanni Li & Lanqin Cao

  5. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, People’s Republic of China

    Xianquan Zhan

  6. Department of Oncology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, People’s Republic of China

    Xianquan Zhan

Authors
  1. Na Li
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  2. Huanni Li
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  3. Ya Wang
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  4. Lanqin Cao
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Contributions

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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Competing interests

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.

Additional information

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 11, 661–694 (2020). https://doi.org/10.1007/s13167-020-00224-z

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