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

  • Translational Research and Biomarkers
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

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.

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Disclosures

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

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Authors and Affiliations

  1. Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan

    Shuichi Fukuda MD, Hiroshi Miyata MD, PhD, Yasuhiro Miyazaki MD, PhD, Tomoki Makino MD, PhD, Tsuyoshi Takahashi MD, PhD, Yukinori Kurokawa MD, PhD, Makoto Yamasaki MD, PhD, Kiyokazu Nakajima MD, PhD, Shuji Takiguchi MD, PhD, Masaki Mori MD, PhD & Yuichiro Doki MD, PhD

Authors
  1. Shuichi Fukuda MD
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  2. Hiroshi Miyata MD, PhD
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  3. Yasuhiro Miyazaki MD, PhD
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  4. Tomoki Makino MD, PhD
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  5. Tsuyoshi Takahashi MD, PhD
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  6. Yukinori Kurokawa MD, PhD
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  7. Makoto Yamasaki MD, PhD
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  8. Kiyokazu Nakajima MD, PhD
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  11. Yuichiro Doki MD, PhD
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Correspondence to Hiroshi Miyata MD, PhD.

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Fukuda, S., Miyata, H., Miyazaki, Y. et al. Pyruvate Kinase M2 Modulates Esophageal Squamous Cell Carcinoma Chemotherapy Response by Regulating the Pentose Phosphate Pathway. Ann Surg Oncol 22 (Suppl 3), 1461–1468 (2015). https://doi.org/10.1245/s10434-015-4522-3

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  • DOI: https://doi.org/10.1245/s10434-015-4522-3

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