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

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.

• Authors: Shuichi Fukuda, Hiroshi Miyata, Yasuhiro Miyazaki, Tomoki Makino, Tsuyoshi Takahashi, Yukinori Kurokawa, Makoto Yamasaki, Kiyokazu Nakajima, Shuji Takiguchi, Masaki Mori, Yuichiro Doki
• Journal: Annals of surgical oncology (Ann Surg Oncol) Vol. 22 Suppl 3 Pg. S1461-8 (Dec 2015) ISSN: 1534-4681 [Electronic] United States
• PMID: 25808097 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Biomarkers, Tumor
• Carrier Proteins
• Membrane Proteins
• RNA, Messenger
• Thyroid Hormones
• thyroid hormone-binding proteins
• Cisplatin

Topics

• Antineoplastic Agents (pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Biomarkers, Tumor (genetics, metabolism)
• Blotting, Western
• Carcinoma, Squamous Cell (drug therapy, metabolism, pathology)
• Carrier Proteins (genetics, metabolism)
• Cell Proliferation (drug effects)
• Cisplatin (pharmacology)
• Drug Resistance, Neoplasm
• Esophageal Neoplasms (drug therapy, metabolism, pathology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Glycolysis (drug effects)
• Humans
• Immunoenzyme Techniques
• Membrane Proteins (genetics, metabolism)
• Neoplasm Invasiveness
• Neoplasm Staging
• Pentose Phosphate Pathway (drug effects)
• Phosphorylation (drug effects)
• Prognosis
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Survival Rate
• Thyroid Hormones (genetics, metabolism)
• Tumor Cells, Cultured