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Pyruvate Kinase Isozyme M2 Plays a Critical Role in the Interactions Between Pancreatic Stellate Cells and Cancer Cells

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Abstract

Background

The interaction between pancreatic cancer cells and pancreatic stellate cells plays a pivotal role in the progression of pancreatic cancer. Pyruvate kinase isozyme M2 is a key enzyme in glycolysis. Previous studies have shown that pyruvate kinase isozyme M2 is overexpressed in pancreatic cancer and that it regulates the aggressive behaviors of pancreatic cancer cells.

Aims

To clarify the role of pyruvate kinase isozyme M2 in the interactions between pancreatic cancer cells and pancreatic stellate cells.

Methods

Pyruvate kinase isozyme M2-knockdown pancreatic cancer cells (Panc-1 and SUIT-2 cells) and pancreatic stellate cells were generated by the introduction of small interfering RNA-expressing vector against pyruvate kinase isozyme M2. Cell proliferation, migration, and epithelial–mesenchymal transition were examined in vitro. The impact of pyruvate kinase isozyme M2 knockdown on the growth of subcutaneous tumors was examined in nude mice in vivo.

Results

Pyruvate kinase isozyme M2-kockdown pancreatic cancer cells and pancreatic stellate cells showed decreased proliferation and migration compared to their respective control cells. Pancreatic stellate cell-induced proliferation, migration, and epithelial–mesenchymal transition were inhibited when pyruvate kinase isozyme M2 expression was knocked down in pancreatic cancer cells. In vivo, co-injection of pancreatic stellate cells increased the size of the tumor developed by the control SUIT-2 cells, but the effects were less evident when pyruvate kinase isozyme M2 was knocked down in SUIT-2 cells or pancreatic stellate cells.

Conclusions

Our results suggested a critical role of pyruvate kinase isozyme M2 in the interaction between pancreatic cancer cells and pancreatic stellate cells.

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Abbreviations

BrdU:

5-Bromo-2′-deoxyuridine

CM:

Conditioned medium

EMT:

Epithelial–mesenchymal transition

OD:

Optical density

PCCs:

Pancreatic cancer cells

PKM2:

Pyruvate kinase isozyme M2

PSCs:

Pancreatic stellate cells

SE:

Standard error

siRNA:

Small interfering RNA

STAT3:

Signal transducer and activator of transcription

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Acknowledgments

The authors are grateful to Shizuka Aoki for the excellent technical assistance.

Funding

This study was supported in part by JSPS (KAKENHI) (26293171, 26461029, 15H04804), the Mitsui Life Social Welfare Foundation (to A. Masamune), the Smoking Research Foundation (to A. Masamune), and the Pancreas Research Foundation of Japan (to N. Yoshida).

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Authors and Affiliations

  1. Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan

    Atsushi Masamune, Shin Hamada, Naoki Yoshida, Tatsuhide Nabeshima & Tooru Shimosegawa

Authors
  1. Atsushi Masamune
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  2. Shin Hamada
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  3. Naoki Yoshida
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  4. Tatsuhide Nabeshima
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  5. Tooru Shimosegawa
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Correspondence to Atsushi Masamune.

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Masamune, A., Hamada, S., Yoshida, N. et al. Pyruvate Kinase Isozyme M2 Plays a Critical Role in the Interactions Between Pancreatic Stellate Cells and Cancer Cells. Dig Dis Sci 63, 1868–1877 (2018). https://doi.org/10.1007/s10620-018-5051-2

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  • DOI: https://doi.org/10.1007/s10620-018-5051-2

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