Knockdown of PKM2 Suppresses Tumor Growth and Invasion in Lung Adenocarcinoma

Int J Mol Sci. 2015 Oct 15;16(10):24574-87. doi: 10.3390/ijms161024574.

Abstract

Accumulating evidence shows that activity of the pyruvate kinase M2 (PKM2) isoform is closely related to tumorigenesis. In this study, we investigated the relationship between PKM2 expression, tumor invasion, and the prognosis of patients with lung adenocarcinoma. We retrospectively analyzed 65 cases of patients with lung adenocarcinoma who were divided into low and a high expression groups based on PKM2 immunohistochemical staining. High PKM2 expression was significantly associated with reduced patient survival. We used small interfering RNA (siRNA) technology to investigate the effect of targeted PKM2-knockout on tumor growth at the cellular level. In vitro, siRNA-mediated PKM2-knockdown significantly inhibited the proliferation, glucose uptake (25%), ATP generation (20%) and fatty acid synthesis of A549 cells, while the mitochondrial respiratory capacity of the cells increased (13%).Western blotting analysis showed that PKM2-knockout significantly inhibited the expression of the glucose transporter GLUT1 and ATP citrate lyase, which is critical for fatty acid synthesis. Further Western blotting analysis showed that PKM2-knockdown inhibited the expression of matrix metalloproteinase 2 (MMP-2) and vascular endothelial growth factor (VEGF), which are important in degradation of the extracellular matrix and angiogenesis, respectively. These observations show that PKM2 activates both glycolysis and lipid synthesis, thereby regulating cell proliferation and invasion. This information is important in elucidating the mechanisms by which PKM2 influences the growth and metastasis of lung adenocarcinoma at the cellular and molecular level, thereby providing the basic data required for the development of PKM2-targeted gene therapy.

Keywords: fatty acid synthesis; glycolysis; invasion; lung adenocarcinoma; pyruvate kinase M2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / metabolism*
  • Adenocarcinoma of Lung
  • Adult
  • Aged
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Cell Proliferation / physiology
  • Female
  • Humans
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism*
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Middle Aged
  • Retrospective Studies
  • Thyroid Hormones / genetics
  • Thyroid Hormones / metabolism*

Substances

  • Carrier Proteins
  • Membrane Proteins
  • Thyroid Hormones
  • thyroid hormone-binding proteins