p38MAPK Signaling Enhances Glycolysis Through the Up-Regulation of the Glucose Transporter GLUT-4 in Gastric Cancer Cells.
OBJECTIVE
Previous studies have shown that p38MAPK is involved in gastric cancer, yet the underlying mechanism remains unclear.


METHODS
q-PCR, Western blot and immunohistochemistry were used to explore the expression of PP2A and the phosphorylation of p38MAPK in gastric cancer tissues and normal gastric tissues. Activated p38MAPK in the gastric cancer cell line MKN45 using activator, then q-PCR, glucose uptake assay and colony formation assay were performed to determine whether p38MAPK promotes gastric cancer through the enhancement of glycolysis. After transfection of p38MAPK dominant negative mutation (p38DN) into MKN45 cells or MKN45 cells treated with an inhibitor of p38MAPK, Western blot was performed to detect the expression of GLUT-4. The knock down of MEF2α in MKN45 cells by siRNA was followed by Western blot and luciferase reporter assay to investigate the underlying mechanism of the role of p38MAPK in the promotion of gastric cancer. Finally, q-PCR, Western blot and immunohistochemistry were performed to examine GLUT-4 expression in gastric cancer tissues and normal gastric tissues.


RESULTS
We found that p38MAPK activation significantly increases GLUT-4 expression and promotes glucose uptake and cell growth in gastric cancer cells. Inhibition of p38MAPK abrogates the up-regulation of GLUT-4. MEF2α knockdown abolishes p38MAPK-mediated GLUT-4 up-regulation. PP2A, an inhibitor of p38MAPK, is down-regulated in gastric cancer tissues, which might contribute to the activation of p38MAPK.


CONCLUSIONS
Our data indicate that the abnormal activation of p38MAPK promotes glycolysis within gastric cancer cells through the upregulation of GLUT-4 in a MEF2a-dependent manner.
Department of General Surgery, the Second Hospital of Jilin University, Changchun, China.
Jingjing
J
Liu
Dacheng
D
Wen
Xuedong
X
Fang
Xudong
X
Wang
Tianzhou
T
Liu
Jiaming
J
Zhu
D045744:Cell Line, Tumor; D049109:Cell Proliferation; D051275:Glucose Transporter Type 4 / Q000235:genetics* / Q000378:metabolism*; D006019:Glycolysis; D006801:Humans; D048669:MAP Kinase Kinase 6 / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D064326:MEF2 Transcription Factors / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
D051275:Glucose Transporter Type 4; D064326:MEF2 Transcription Factors; C578035:MEF2A protein, human; C495692:SLC2A4 protein, human; D048669:MAP Kinase Kinase 6; C482566:MAP2K6 protein, human; D054648:Protein Phosphatase 2