A combined proteomics and metabolomics profiling of gastric cardia cancer reveals characteristic dysregulations in glucose metabolism.
Gastric cardia cancer (GCC), which occurs at the gastric-esophageal boundary, is one of the most malignant tumors. Despite its high mortality and morbidity, the molecular mechanism of initiation and progression of this disease is largely unknown. In this study, using proteomics and metabolomics approaches, we found that the level of several enzymes and their related metabolic intermediates involved in glucose metabolism were deregulated in GCC. Among these enzymes, two subunits controlling pyruvic acid efflux, lactate dehydrogenase A (LDHA) and pyruvate dehydrogenase B (PDHB), were further analyzed in vitro. Either down-regulation of LDH subunit LDHA or overexpression of PDH subunit PDHB could force pyruvic acid into the Krebs cycle rather than the glycolysis process in AGS gastric cancer cells, which inhibited cell growth and cell migration. Our results reflect an important glucose metabolic signature, especially the dysregulation of pyruvic acid efflux in the development of GCC. Forced transition from glycolysis to the Krebs cycle had an inhibitory effect on GCC progression, providing potential therapeutic targets for this disease.
Cai
Zhen
Z
Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Graduate School of the Chinese Academy of Sciences, Shanghai 200031, China.
Zhao
Jiang-Sha
JS
Li
Jing-Jing
JJ
Peng
Dan-Ni
DN
Wang
Xiao-Yan
XY
Chen
Tian-Lu
TL
Qiu
Yun-Ping
YP
Chen
Ping-Ping
PP
Li
Wen-Jie
WJ
Xu
Li-Yan
LY
Li
En-Ming
EM
Tam
Jason P M
JP
Qi
Robert Z
RZ
Jia
Wei
W
Xie
Dong
D
D001483:Base Sequence; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D002952:Citric Acid Cycle; D017931:DNA Primers; D015180:Electrophoresis, Gel, Two-Dimensional; D005260:Female; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000235:genetics; D008297:Male; D055432:Metabolomics; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D040901:Proteomics; D011768:Pyruvate Dehydrogenase Complex / Q000235:genetics; D034622:RNA Interference; D013274:Stomach Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology
D017931:DNA Primers; D011768:Pyruvate Dehydrogenase Complex; D007770:L-Lactate Dehydrogenase; D005947:Glucose