Citrate synthase expression affects tumor phenotype and drug resistance in human ovarian carcinoma

Lilan Chen; Ting Liu; Jinhua Zhou; Yunfei Wang; Xinran Wang; Wen Di; Shu Zhang

doi:10.1371/journal.pone.0115708

Citrate synthase expression affects tumor phenotype and drug resistance in human ovarian carcinoma

PLoS One. 2014 Dec 29;9(12):e115708. doi: 10.1371/journal.pone.0115708. eCollection 2014.

Authors

Lilan Chen¹, Ting Liu¹, Jinhua Zhou¹, Yunfei Wang¹, Xinran Wang¹, Wen Di¹, Shu Zhang¹

Affiliation

¹ Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China; Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, 200127, P. R. China.

Abstract

Citrate synthase (CS), one of the key enzymes in the tricarboxylic acid (TCA) cycle, catalyzes the reaction between oxaloacetic acid and acetyl coenzyme A to generate citrate. Increased CS has been observed in pancreatic cancer. In this study, we found higher CS expression in malignant ovarian tumors and ovarian cancer cell lines compared to benign ovarian tumors and normal human ovarian surface epithelium, respectively. CS knockdown by RNAi could result in the reduction of cell proliferation, and inhibition of invasion and migration of ovarian cancer cells in vitro. The drug resistance was also inhibited possibly through an excision repair cross complementing 1 (ERCC1)-dependent mechanism. Finally, upon CS knockdown we observed significant increase expression of multiple genes, including ISG15, IRF7, CASP7, and DDX58 in SKOV3 and A2780 cells by microarray analysis and real-time PCR. Taken together, these results suggested that CS might represent a potential therapeutic target for ovarian carcinoma.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinases / metabolism
Adenosine Triphosphate / metabolism
Antineoplastic Agents / pharmacology
Apoptosis / drug effects
Carcinoma, Ovarian Epithelial
Cell Line, Tumor
Cell Movement / drug effects
Cell Proliferation / drug effects
Cisplatin / pharmacology
Citrate (si)-Synthase / genetics*
Citrate (si)-Synthase / metabolism*
Drug Resistance / drug effects*
Female
Gene Knockdown Techniques
Humans
Neoplasm Invasiveness
Neoplasms, Glandular and Epithelial / metabolism*
Neoplasms, Glandular and Epithelial / pathology*
Ovarian Neoplasms / metabolism*
Ovarian Neoplasms / pathology*
Phenotype*
RNA, Small Interfering / pharmacology
p38 Mitogen-Activated Protein Kinases / metabolism

Substances

Antineoplastic Agents
RNA, Small Interfering
Adenosine Triphosphate
Citrate (si)-Synthase
p38 Mitogen-Activated Protein Kinases
AMP-Activated Protein Kinases
Cisplatin

Grants and funding

This work was supported by Shanghai Committee of Science and Technology (Grant No. 10dz2212100 and Grant No. 12411950200 to Wen Di), National Natural Science Foundation (Grant No. 81072137 to Wen Di, Grant No. 81172479 to Shu Zhang), Shanghai Health Bureau Key Disciplines and Specialties Foundation, Shanghai Education Commission Key Disciplines Foundation, the Key Discipline Project of Ren Ji Hospital, and the Shanghai Jiao Tong University School of Medicine. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.