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PLoS One. 2017 Jul 28;12(7):e0182166. doi: 10.1371/journal.pone.0182166. eCollection 2017.

Pyruvate kinase M2 is a poor prognostic marker of and a therapeutic target in ovarian cancer.

Chao TK1,2,3, Huang TS3,4,5, Liao YP3,4,5, Huang RL3,4,5, Su PH3,4,5, Shen HY6, Lai HC1,3,4,5, Wang YC1,3,7.

Author information

1
Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.
2
Department of Pathology, Tri-Service General Hospital, National Defense Medical Centre, Taipei, Taiwan.
3
Laboratory of Epigenetics and Cancer Stem Cells, National Defense Medical Centre, Taipei, Taiwan.
4
Department of Obstetrics and Gynecology, Shuang-Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.
5
Department of Obstetrics and Gynecology, School of medicine, College of medicine, Taipei Medical University, Taipei, Taiwan.
6
Department of Nuclear Medicine and PET center, Tri-Service General Hospital, National Defense Medical Centre, Taipei, Taiwan.
7
Department of Obstetrics and Gynecology, Tri-Service General Hospital, National Defense Medical Centre, Taipei, Taiwan.

Abstract

Pyruvate kinase M2 (PKM2) regulates glycolysis and oxidative phosphorylation; however, the role of PKM2 in ovarian cancer remains largely unknown. We investigated whether ovarian cancer metabolism could provide insight into the development of therapeutic strategies. We performed immunohistochemical staining for PKM2 on a tissue microarray for multivariate analysis. It revealed that patients exhibiting higher PKM2 expression were significantly associated with malignancy groups (p < 0.001) and pathogenesis models (p < 0.001), had poor progression-free survival rates (p = 0.01) as compared with patients exhibiting lower PKM2 levels, and yielded a hazard ratio of death of 2.02 (95% confidence interval: 0.70-5.85). In cell lines, PKM2 inhibitor significantly inhibited the glycolytic rate according to cellular glucose consumption (p < 0.001). We also utilized Seahorse assays to assess metabolism-related cell-specific factors and the impact of PKM2 inhibitors. Energy shifts as per Seahorse analysis showed attenuation of the extracellular acidification rate (p < 0.05) and no significant difference in oxygen-consumption rate in SKOV3 cells. Treatment with PKM2 inhibitor suppressed ovarian cancer growth and cell migration in vitro and inhibited tumor growth without significant toxicity in a xenograft study. PKM2 inhibition disturbed Warburg effects and inhibited ovarian cancer cell growth. Targeting PKM2 may constitute a promising therapy for patients with ovarian cancer, and clinical trials involving shikonin are warranted.

PMID:
28753677
PMCID:
PMC5533430
DOI:
10.1371/journal.pone.0182166
[Indexed for MEDLINE]
Free PMC Article

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