Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Oncology Letters
      • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Biomedical Reports
      • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • Information for Authors
    • Information for Reviewers
    • Information for Librarians
    • Information for Advertisers
    • Conferences
  • Language Editing
Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • For Authors
    • For Reviewers
    • For Librarians
    • For Advertisers
    • Conferences
  • Language Editing
Login Register Submit
  • This site uses cookies
  • You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy.

    I agree
Search articles by DOI, keyword, author or affiliation
Search
Advanced Search
presentation
International Journal of Oncology
Join Editorial Board Propose a Special Issue
Print ISSN: 1019-6439 Online ISSN: 1791-2423
Journal Cover
March-2018 Volume 52 Issue 3

Full Size Image

Cover Legend PDF

Sign up for eToc alerts
Recommend to Library

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

Medicine International

An International Open Access Journal Devoted to General Medicine.

Journal Cover
March-2018 Volume 52 Issue 3

Full Size Image

Cover Legend PDF

Sign up for eToc alerts
Recommend to Library

  • Article
  • Citations
    • Cite This Article
    • Download Citation
    • Create Citation Alert
    • Remove Citation Alert
    • Cited By
  • Similar Articles
    • Related Articles (in Spandidos Publications)
    • Similar Articles (Google Scholar)
    • Similar Articles (PubMed)
  • Download PDF
  • Download XML
  • View XML
Article

Pyruvate kinase type M2 contributes to the development of pancreatic ductal adenocarcinoma by regulating the production of metabolites and reactive oxygen species

  • Authors:
    • Misa Yokoyama
    • Nobuhiro Tanuma
    • Rie Shibuya
    • Takeharu Shiroki
    • Makoto Abue
    • Kuniharu Yamamoto
    • Koh Miura
    • Kazunori Yamaguchi
    • Ikuro Sato
    • Keiichi Tamai
    • Kennichi Satoh
  • View Affiliations / Copyright

    Affiliations: Division of Cancer Stem Cell, Miyagi Cancer Center Research Institute, Natori, Miyagi 981-1293, Japan, Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Natori, Miyagi 981-1293, Japan, Department of Gastroenterology, Miyagi Cancer Center, Natori, Miyagi 981-1293, Japan, Department of Gastroenterological Surgery, Miyagi Cancer Center, Natori, Miyagi 981-1293, Japan, Division of Molecular and Cellular Oncology, Miyagi Cancer Center Research Institute, Natori, Miyagi 981-1293, Japan, Department of Pathology, Miyagi Cancer Center, Natori, Miyagi 981-1293, Japan
  • Pages: 881-891
    |
    Published online on: January 30, 2018
       https://doi.org/10.3892/ijo.2018.4258
  • Expand metrics +
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
Cited By (CrossRef): 0 citations Loading Articles...

This article is mentioned in:



Abstract

The majority of cancer cells maintain a high glycolytic activity and an increased lactate production, even in a well oxygenated environment. This phenomenon is known as the Warburg effect. Previous studies have revealed that various types of cancer selectively express the pyruvate kinase M2 isoform (PKM2), and that PKM2 plays a pivotal role in the Warburg effect. Although elevated PKM2 levels have been observed in pancreatic cancer and other types of cancer, little is known about the biological function of PKM2. In this study, in order to examine the expression and role of PKM2 in pancreatic ductal adenocarcinoma (PDAC), we knocked down PKM2 in PDAC cells by introducing small interfering and short hairpin RNAs, and examined the gene expression profiles in the cells by microarray analysis. We analyzed the energy-producing pathways in the cells by XFe Extracellular Flux Analyzers, and detected intracellular metabolites by capillary electrophoresis time-of-flight mass spectrometry. We found that the RNAi-mediated knockdown of PKM2 diminished the proliferative, migratory and tumorigenic ability of the PDAC cell-lines. PKM2 knockdown also resulted in lower glycolytic activities and decreased levels of some intracellular metabolites, such as pyruvate and polyamine; however, it led to elevated levels of reactive oxygen species. Microarray analysis revealed the functional association between PKM2 and the expression of genes that drive the cell cycle. On the whole, the findings of this study demonstrate that PKM2 plays an important role in metabolic activities, as well as in the malignancy of PDAC cells.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

View References

1 

Ma J, Siegel R and Jemal A: Pancreatic cancer death rates by race among US men and women, 1970–2009. J Natl Cancer Inst. 105:1694–1700. 2013. View Article : Google Scholar : PubMed/NCBI

2 

Vander Heiden MG, Cantley LC and Thompson CB: Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science. 324:1029–1033. 2009. View Article : Google Scholar : PubMed/NCBI

3 

Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, Fleming MD, Schreiber SL and Cantley LC: The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature. 452:230–233. 2008. View Article : Google Scholar : PubMed/NCBI

4 

Mazurek S: Pyruvate kinase type M2: A key regulator of the metabolic budget system in tumor cells. Int J Biochem Cell Biol. 43:969–980. 2011. View Article : Google Scholar

5 

Marie J, Levin MJ, Simon MP and Kahn A: Genetic and epigenetic control of the pyruvate kinase isozymes in mammals. Isozymes Curr Top Biol Med Res. 7:221–240. 1983.PubMed/NCBI

6 

Dong G, Mao Q, Xia W, Xu Y, Wang J, Xu L and Jiang F: PKM2 and cancer: The function of PKM2 beyond glycolysis. Oncol Lett. 11:1980–1986. 2016. View Article : Google Scholar : PubMed/NCBI

7 

Li C, Zhao Z, Zhou Z and Liu R: PKM2 promotes cell survival and invasion under metabolic stress by enhancing Warburg effect in pancreatic ductal adenocarcinoma. Dig Dis Sci. 61:767–773. 2016. View Article : Google Scholar

8 

Yang W, Xia Y, Cao Y, Zheng Y, Bu W, Zhang L, You MJ, Koh MY, Cote G, Aldape K, et al: EGFR-induced and PKCε monoubiquitylation-dependent NF-κB activation upregulates PKM2 expression and promotes tumorigenesis. Mol Cell. 48:771–784. 2012. View Article : Google Scholar : PubMed/NCBI

9 

Wong N, Ojo D, Yan J and Tang D: PKM2 contributes to cancer metabolism. Cancer Lett. 356:184–191. 2015. View Article : Google Scholar

10 

Luo W, Hu H, Chang R, Zhong J, Knabel M, O'Meally R, Cole RN, Pandey A and Semenza GL: Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell. 145:732–744. 2011. View Article : Google Scholar : PubMed/NCBI

11 

Yang W, Xia Y, Hawke D, Li X, Liang J, Xing D, Aldape K, Hunter T, Alfred Yung WK and Lu Z: PKM2 phosphorylates histone H3 and promotes gene transcription and tumorigenesis. Cell. 150:685–696. 2012. View Article : Google Scholar : PubMed/NCBI

12 

Goldberg MS and Sharp PA: Pyruvate kinase M2-specific siRNA induces apoptosis and tumor regression. J Exp Med. 209:217–224. 2012. View Article : Google Scholar : PubMed/NCBI

13 

Bell SP and Dutta A: DNA replication in eukaryotic cells. Annu Rev Biochem. 71:333–374. 2002. View Article : Google Scholar : PubMed/NCBI

14 

Pegg AE: Spermidine/spermine-N(1)-acetyltransferase: A key metabolic regulator. Am J Physiol Endocrinol Metab. 294:E995–E1010. 2008. View Article : Google Scholar : PubMed/NCBI

15 

Lockney NA, Zhang M, Lu Y, Sopha SC, Washington MK, Merchant N, Zhao Z, Shyr Y, Chakravarthy AB and Xia F: Pyruvate kinase muscle isoenzyme 2 (PKM2) expression is associated with overall survival in pancreatic ductal adenocarcinoma. J Gastrointest Cancer. 46:390–398. 2015. View Article : Google Scholar : PubMed/NCBI

16 

Pegg AE: Polyamine metabolism and its importance in neoplastic growth and a target for chemotherapy. Cancer Res. 48:759–774. 1988.PubMed/NCBI

17 

Pegg AE: Mammalian polyamine metabolism and function. IUBMB Life. 61:880–894. 2009. View Article : Google Scholar : PubMed/NCBI

18 

Childs AC, Mehta DJ and Gerner EW: Polyamine-dependent gene expression. Cell Mol Life Sci. 60:1394–1406. 2003. View Article : Google Scholar : PubMed/NCBI

19 

Nowotarski SL, Woster PM and Casero RA Jr: Polyamines and cancer: Implications for chemotherapy and chemoprevention. Expert Rev Mol Med. 15:e32013. View Article : Google Scholar : PubMed/NCBI

20 

Takigawa M, Verma AK, Simsiman RC and Boutwell RK: Inhibition of mouse skin tumor promotion and of promoter-stimulated epidermal polyamine biosynthesis by alpha-difluoromethylornithine. Cancer Res. 43:3732–3738. 1983.PubMed/NCBI

21 

Gupta ED, Pachauri M, Ghosh PC and Rajam MV: Targeting polyamine biosynthetic pathway through RNAi causes the abrogation of MCF 7 breast cancer cell line. Tumour Biol. 37:1159–1171. 2016. View Article : Google Scholar

22 

Russell DH: Increased polyamine concentrations in the urine of human cancer patients. Nat New Biol. 233:144–145. 1971. View Article : Google Scholar : PubMed/NCBI

23 

Krüger A, Vowinckel J, Mülleder M, Grote P, Capuano F, Bluemlein K and Ralser M: Tpo1-mediated spermine and spermidine export controls cell cycle delay and times antioxidant protein expression during the oxidative stress response. EMBO Rep. 14:1113–1119. 2013. View Article : Google Scholar : PubMed/NCBI

24 

Cross CE, Halliwell B, Borish ET, Pryor WA, Ames BN, Saul RL, McCord JM and Harman D: Oxygen radicals and human disease. Ann Intern Med. 107:526–545. 1987. View Article : Google Scholar : PubMed/NCBI

25 

Chio IIC and Tuveson DA: ROS in cancer: The burning question. Trends Mol Med. 23:411–429. 2017. View Article : Google Scholar : PubMed/NCBI

26 

Liou GY and Storz P: Reactive oxygen species in cancer. Free Radic Res. 44:479–496. 2010. View Article : Google Scholar : PubMed/NCBI

27 

Galadari S, Rahman A, Pallichankandy S and Thayyullathil F: Reactive oxygen species and cancer paradox: To promote or to suppress? Free Radic Biol Med. 104:144–164. 2017. View Article : Google Scholar : PubMed/NCBI

28 

Diehn M, Cho RW, Lobo NA, Kalisky T, Dorie MJ, Kulp AN, Qian D, Lam JS, Ailles LE, Wong M, et al: Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature. 458:780–783. 2009. View Article : Google Scholar : PubMed/NCBI

29 

Zheng B, Peng J, Mollayup A, Bakri A, Guo L, Zheng J and Xu H: Construction of a prognostic prediction system for pancreatic ductal adenocarcinoma to investigate the key prognostic genes. Mol Med Rep. 17:216–224. 2018.

30 

Badea L, Herlea V, Dima SO, Dumitrascu T and Popescu I: Combined gene expression analysis of whole-tissue and microdissected pancreatic ductal adenocarcinoma identifies genes specifically overexpressed in tumor epithelia. Hepatogastroenterology. 55:2016–2027. 2008.

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Yokoyama M, Tanuma N, Shibuya R, Shiroki T, Abue M, Yamamoto K, Miura K, Yamaguchi K, Sato I, Tamai K, Tamai K, et al: Pyruvate kinase type M2 contributes to the development of pancreatic ductal adenocarcinoma by regulating the production of metabolites and reactive oxygen species. Int J Oncol 52: 881-891, 2018.
APA
Yokoyama, M., Tanuma, N., Shibuya, R., Shiroki, T., Abue, M., Yamamoto, K. ... Satoh, K. (2018). Pyruvate kinase type M2 contributes to the development of pancreatic ductal adenocarcinoma by regulating the production of metabolites and reactive oxygen species. International Journal of Oncology, 52, 881-891. https://doi.org/10.3892/ijo.2018.4258
MLA
Yokoyama, M., Tanuma, N., Shibuya, R., Shiroki, T., Abue, M., Yamamoto, K., Miura, K., Yamaguchi, K., Sato, I., Tamai, K., Satoh, K."Pyruvate kinase type M2 contributes to the development of pancreatic ductal adenocarcinoma by regulating the production of metabolites and reactive oxygen species". International Journal of Oncology 52.3 (2018): 881-891.
Chicago
Yokoyama, M., Tanuma, N., Shibuya, R., Shiroki, T., Abue, M., Yamamoto, K., Miura, K., Yamaguchi, K., Sato, I., Tamai, K., Satoh, K."Pyruvate kinase type M2 contributes to the development of pancreatic ductal adenocarcinoma by regulating the production of metabolites and reactive oxygen species". International Journal of Oncology 52, no. 3 (2018): 881-891. https://doi.org/10.3892/ijo.2018.4258
Copy and paste a formatted citation
x
Spandidos Publications style
Yokoyama M, Tanuma N, Shibuya R, Shiroki T, Abue M, Yamamoto K, Miura K, Yamaguchi K, Sato I, Tamai K, Tamai K, et al: Pyruvate kinase type M2 contributes to the development of pancreatic ductal adenocarcinoma by regulating the production of metabolites and reactive oxygen species. Int J Oncol 52: 881-891, 2018.
APA
Yokoyama, M., Tanuma, N., Shibuya, R., Shiroki, T., Abue, M., Yamamoto, K. ... Satoh, K. (2018). Pyruvate kinase type M2 contributes to the development of pancreatic ductal adenocarcinoma by regulating the production of metabolites and reactive oxygen species. International Journal of Oncology, 52, 881-891. https://doi.org/10.3892/ijo.2018.4258
MLA
Yokoyama, M., Tanuma, N., Shibuya, R., Shiroki, T., Abue, M., Yamamoto, K., Miura, K., Yamaguchi, K., Sato, I., Tamai, K., Satoh, K."Pyruvate kinase type M2 contributes to the development of pancreatic ductal adenocarcinoma by regulating the production of metabolites and reactive oxygen species". International Journal of Oncology 52.3 (2018): 881-891.
Chicago
Yokoyama, M., Tanuma, N., Shibuya, R., Shiroki, T., Abue, M., Yamamoto, K., Miura, K., Yamaguchi, K., Sato, I., Tamai, K., Satoh, K."Pyruvate kinase type M2 contributes to the development of pancreatic ductal adenocarcinoma by regulating the production of metabolites and reactive oxygen species". International Journal of Oncology 52, no. 3 (2018): 881-891. https://doi.org/10.3892/ijo.2018.4258
Follow us
  • Twitter
  • LinkedIn
  • Facebook
About
  • Spandidos Publications
  • Careers
  • Cookie Policy
  • Privacy Policy
How can we help?
  • Help
  • Live Chat
  • Contact
  • Email to our Support Team