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Annals of Surgical Oncology

, Volume 22, Supplement 3, pp 1461–1468 | Cite as

Pyruvate Kinase M2 Modulates Esophageal Squamous Cell Carcinoma Chemotherapy Response by Regulating the Pentose Phosphate Pathway

  • Shuichi Fukuda
  • Hiroshi Miyata
  • Yasuhiro Miyazaki
  • Tomoki Makino
  • Tsuyoshi Takahashi
  • Yukinori Kurokawa
  • Makoto Yamasaki
  • Kiyokazu Nakajima
  • Shuji Takiguchi
  • Masaki Mori
  • Yuichiro Doki
Translational Research and Biomarkers

Abstract

Background

Pyruvate kinase M2 (PKM2) is a key glycolytic enzyme that regulates the Warburg effect and is necessary for tumor growth. However, its role in chemoresistance has not been fully elucidated.

Methods

PKM2 expression was examined by immunohistochemistry in 205 tissue samples from thoracic esophageal squamous cell carcinoma patients who had undergone curative surgery (100 patients with surgery alone and 105 patients with preoperative chemotherapy). The relationship between PKM2 expression and clinicopathological factors, including chemotherapy response was examined. In vitro assays were performed to determine the mechanism of PKM2-related chemoresistance, using esophageal squamous cell carcinoma cell lines.

Results

PKM2 expression significantly correlated with tumor cell differentiation, tumor depth, and tumor stage. Strong PKM2 expression significantly correlated with decreased survival rates and poor response to chemotherapy. In vitro assays showed that PKM2 inhibition significantly decreased cisplatin resistance and increased apoptosis. In siPKM2-transfected cells, pyruvate kinase activity paradoxically increased, followed by increased intracellular reactive oxygen species levels. The ratio of NADPH/NADP, which is an indicator of glucose influx into pentose phosphate pathway (PPP), significantly decreased in siPKM2-transfected cells upon cisplatin treatment compared with control cells.

Conclusions

PKM2 expression is associated with esophageal squamous cell carcinoma chemoresistance. PKM2 inhibition can restore cisplatin sensitivity by inactivating PPP.

Keywords

Esophageal Squamous Cell Carcinoma Intracellular Reactive Oxygen Species Pentose Phosphate Pathway Pyruvate Kinase Esophageal Squamous Cell Carcinoma Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Disclosures

The authors declare no conflicts of interest or financial ties to disclose in relation to this study.

Supplementary material

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Copyright information

© Society of Surgical Oncology 2015

Authors and Affiliations

  • Shuichi Fukuda
    • 1
  • Hiroshi Miyata
    • 1
  • Yasuhiro Miyazaki
    • 1
  • Tomoki Makino
    • 1
  • Tsuyoshi Takahashi
    • 1
  • Yukinori Kurokawa
    • 1
  • Makoto Yamasaki
    • 1
  • Kiyokazu Nakajima
    • 1
  • Shuji Takiguchi
    • 1
  • Masaki Mori
    • 1
  • Yuichiro Doki
    • 1
  1. 1.Department of Gastroenterological SurgeryOsaka University Graduate School of MedicineOsakaJapan

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