Skip to main content


Log in

PKM2 Promotes Cell Survival and Invasion Under Metabolic Stress by Enhancing Warburg Effect in Pancreatic Ductal Adenocarcinoma

  • Original Article
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

    We’re sorry, something doesn't seem to be working properly.

    Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.



Pyruvate kinase isoenzyme M2 (PKM2) is an essential enzyme involved in the regulation of aerobic glycolysis in cancer cells and promotes the translation between glycolytic flux and biosynthesis of cellular building blocks.


Our present study aims to explore the expression pattern and underlying cellular functions of PKM2 in pancreatic ductal adenocarcinoma (PDAC) under metabolic stress.


Oncomine database and a tissue microarray (n = 90) were used to investigate the expression pattern of PKM2 and its clinicopathological findings. In vitro proliferation, apoptosis and invasion assays were used to determine the role and related mechanism of PKM2 in PDAC.


Data from Oncomine database and our tissue microarray show that PKM2 is significantly elevated in PDAC specimens compared with the corresponding normal tissues. Kaplan–Meier survival analysis shows that higher expression of PKM2 is closely correlated with a poor prognosis of patients with PDAC. Under metabolic stress, suppression of PKM2 expression in PANC-1 and AsPC-1 cells results in decreased cell survival, increased caspase-3/7 activity, and reduced invasive potential, and these effects can be reversed by reintroduction of PKM2. Furthermore, sh-PKM2 cells show a significant decreased Warburg effect compared with sh-Ctrl cells as demonstrated by reduced glucose consumption and lactate production. Treatment with 2-deoxy-d-glucose, a glycolysis inhibitor, completely blocks the influences of PKM2 on cell survival and invasion.


Our study reveals that silencing of PKM2 exhibits a tumor-suppressive role through altered Warburg effect and suggests that targeting PKM2 might serve as a potential therapeutic target for PDAC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others


  1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108.

    Article  PubMed  Google Scholar 

  2. Vincent A, Herman J, Schulick R, Hruban RH, Goggins M. Pancreatic cancer. Lancet. 2011;378:607–620.

    Article  PubMed Central  PubMed  Google Scholar 

  3. Raimondi S, Maisonneuve P, Lowenfels AB. Epidemiology of pancreatic cancer: an overview Nature reviews. Gastroenterol Hepatol. 2009;6:699–708.

    Google Scholar 

  4. Hartwig W, Werner J, Jager D, Debus J, Buchler MW. Improvement of surgical results for pancreatic cancer. Lancet Oncol. 2013;14:e476–e485.

    Article  PubMed  Google Scholar 

  5. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–674.

    Article  CAS  PubMed  Google Scholar 

  6. Gruning NM, Rinnerthaler M, Bluemlein K, et al. Pyruvate kinase triggers a metabolic feedback loop that controls redox metabolism in respiring cells. Cell Metab. 2011;14:415–427.

    Article  PubMed Central  PubMed  Google Scholar 

  7. Noguchi T, Inoue H, Tanaka T. The M1- and M2-type isozymes of rat pyruvate kinase are produced from the same gene by alternative RNA splicing. J Biol Chem. 1986;261:13807–13812.

    CAS  PubMed  Google Scholar 

  8. Noguchi T, Yamada K, Inoue H, Matsuda T, Tanaka T. The L- and R-type isozymes of rat pyruvate kinase are produced from a single gene by use of different promoters. J Biol Chem. 1987;262:14366–14371.

    CAS  PubMed  Google Scholar 

  9. Chen Z, Lu X, Wang Z, et al. Co-expression of PKM2 and TRIM35 predicts survival and recurrence in hepatocellular carcinoma. Oncotarget. 2015;6:2538–2548.

    PubMed  Google Scholar 

  10. Liu WR, Tian MX, Yang LX, et al. PKM2 promotes metastasis by recruiting myeloid-derived suppressor cells and indicates poor prognosis for hepatocellular carcinoma. Oncotarget. 2015;6:846–861.

    Article  PubMed Central  PubMed  Google Scholar 

  11. Yuan C, Li Z, Wang Y, et al. Overexpression of metabolic markers PKM2 and LDH5 correlates with aggressive clinicopathological features and adverse patient prognosis in tongue cancer. Histopathology. 2014;65:595–605.

    Article  PubMed  Google Scholar 

  12. Yang W, Xia Y, Ji H, et al. Nuclear PKM2 regulates beta-catenin transactivation upon EGFR activation. Nature. 2011;480:118–122.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Yang P, Li Z, Wang Y, Zhang L, Wu H, Li Z. Secreted pyruvate kinase M2 facilitates cell migration via PI3K/Akt and Wnt/beta-catenin pathway in colon cancer cells. Biochem Biophys Res Commun. 2015;459:327–332.

    Article  CAS  PubMed  Google Scholar 

  14. Li J, Yang Z, Zou Q, et al. PKM2 and ACVR 1C are prognostic markers for poor prognosis of gallbladder cancer. Clin Transl Oncol. 2014;16:200–207.

    Article  PubMed  Google Scholar 

  15. Zhan C, Shi Y, Lu C, Wang Q. Pyruvate kinase M2 is highly correlated with the differentiation and the prognosis of esophageal squamous cell cancer. Dis Esophagus. 2013;26:746–753.

    CAS  PubMed  Google Scholar 

  16. Hu W, Lu SX, Li M, et al. Pyruvate kinase M2 prevents apoptosis via modulating Bim stability and associates with poor outcome in hepatocellular carcinoma. Oncotarget. 2015;6:6570–6583.

    Article  PubMed Central  PubMed  Google Scholar 

  17. Yang W, Lu Z. Regulation and function of pyruvate kinase M2 in cancer. Cancer Lett. 2013;339:153–158.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Dong T, Yan Y, Chai H, et al. Pyruvate kinase M2 affects liver cancer cell behavior through up-regulation of HIF-1alpha and Bcl-xL in culture. Biomed Pharmacother. 2015;69:277–284.

    Article  CAS  PubMed  Google Scholar 

  19. Wong N, Ojo D, Yan J, Tang D. PKM2 contributes to cancer metabolism. Cancer Lett. 2015;356:184–191.

    Article  CAS  PubMed  Google Scholar 

  20. Jiang Y, Li X, Yang W, et al. PKM2 regulates chromosome segregation and mitosis progression of tumor cells. Mol Cell. 2014;53:75–87.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Gali P, Bourdin M. Ontogenesis of pyruvate kinase in the brain and liver tissues of the rat. Biochimie. 1978;60:1253–1260.

    Article  CAS  PubMed  Google Scholar 

  22. Reinacher M, Eigenbrodt E. Immunohistological demonstration of the same type of pyruvate kinase isoenzyme (M2-Pk) in tumors of chicken and rat. Virchows Archiv B Cell Pathol Incl Mol Pathol. 1981;37:79–88.

    Article  CAS  Google Scholar 

  23. Max-Audit I, Testa U, Kechemir D, Titeux M, Vainchenker W, Rosa R. Pattern of pyruvate kinase isozymes in erythroleukemia cell lines and in normal human erythroblasts. Blood. 1984;64:930–936.

    CAS  PubMed  Google Scholar 

  24. Luo W, Semenza GL. Emerging roles of PKM2 in cell metabolism and cancer progression. Trends Endocrinol Metab. 2012;23:560–566.

    Article  PubMed Central  PubMed  Google Scholar 

  25. Zhao Y, Shen L, Chen X, et al. High expression of PKM2 as a poor prognosis indicator is associated with radiation resistance in cervical cancer. Histol Histopathol. 2015;30:1313–1320.

    PubMed  Google Scholar 

  26. Chen L, Shi Y, Liu S, Cao Y, Wang X, Tao Y. PKM2: the thread linking energy metabolism reprogramming with epigenetics in cancer. Int J Mol Sci. 2014;15:11435–11445.

    Article  PubMed Central  PubMed  Google Scholar 

  27. Chiavarina B, Whitaker-Menezes D, Martinez-Outschoorn UE, et al. Pyruvate kinase expression (PKM1 and PKM2) in cancer-associated fibroblasts drives stromal nutrient production and tumor growth. Cancer Biol Ther. 2011;12:1101–1113.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Macintyre AN, Rathmell JC. PKM2 and the tricky balance of growth and energy in cancer. Mol Cell. 2011;42:713–714.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Papadaki C, Sfakianaki M, Lagoudaki E, et al. PKM2 as a biomarker for chemosensitivity to front-line platinum-based chemotherapy in patients with metastatic non-small-cell lung cancer. Br J Cancer. 2014;111:1757–1764.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Feng J, Ma T, Ge Z, et al. PKM2 gene regulates the behavior of pancreatic cancer cells via mitogen-activated protein kinase pathways. Mol Med Rep. 2015;11:2111–2117.

    CAS  PubMed  Google Scholar 

  31. VanderHeiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324:1029–1033.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations


Corresponding author

Correspondence to Chenggang Li.

Ethics declarations

Conflict of interest

The authors declare that there is no conflict of interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, C., Zhao, Z., Zhou, Z. et al. PKM2 Promotes Cell Survival and Invasion Under Metabolic Stress by Enhancing Warburg Effect in Pancreatic Ductal Adenocarcinoma. Dig Dis Sci 61, 767–773 (2016).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: