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 betweenPKM2 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 PKM2immunohistochemical 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.
Highlights
IntroductionGlucose metabolism is highly active during tumorigenesis. This particular biological characteristic of the tumor, which is called the “Warburg effect”, is considered to be the seventh characteristic sign of tumors [1]
Unlike most normal cells, glucose metabolism is highly active during tumorigenesis
This information is important in elucidating the mechanisms by which pyruvate kinase M2 (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
Summary
Glucose metabolism is highly active during tumorigenesis. This particular biological characteristic of the tumor, which is called the “Warburg effect”, is considered to be the seventh characteristic sign of tumors [1]. Glycolysis activation in turn promotes increased expression of some oncogenes, forming a positive feedback loop between oncogene activation and glycolysis This positive feedback mechanism results in the malignant transformation of tumor cells, which is associated with enhanced invasion capacity and resistance to chemotherapy [7,8]. Investigated the characteristics of PKM2 expression as well as the relationship between PKM2 expression, tumor invasion, and the prognosis of patients with lung adenocarcinoma 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
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