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.Gastric cardia cancer (GCC),1 which occurs at the gastric-esophageal boundary, is one of the most malignant tumors. Despite the steadily falling incidence of gastric non-cardia cancer in the past two decades (1), the rate of GCC has risen rapidly, establishing gastric cancer as the second major cause of cancer-related deaths throughout the world (2). GCC has become a significant cause of mortality and morbidity both in the west (3–5) and in Asia (6, 7), especially in China (8). Although this cancer has become an important health problem worldwide, the its pathogenesis has not been well characterized (1). Most patients are diagnosed at an advanced stage, contributing to the high mortality rate of the disease.Systematic proteomics analysis has proved to be a powerful approach in a variety of human cancer research, including lung (9), esophagus (10), gastric (11), liver (12), breast (13), and brain cancer (14). Metabolomics, another new bio-omics technology recently introduced into cancer research (15), is the global analysis of the small metabolites produced by normal or pathologic cellular processes. Some metabolic intermediates have been identified as new cancer biomarkers (16).Using proteomics and metabolomics methods in this study, we found that a series of proteins and metabolic intermediates, mainly involved in glucose metabolism, were altered during the development of GCC. The high activity of anaerobic glycolysis and the impairment of aerobic respiration occurring in these cells recapitulated the Warburg effect (17). Further studies using a gastric cancer cell line demonstrated that the predominant anaerobic glycolysis was essential for tumor cells to sustain rapid proliferation, whereas forced transition from anaerobic glycolysis to aerobic respiration inhibited the growth of tumor cells. In conclusion, our study revealed the major metabolic alterations essential for the development of GCC and discovered a biomarker signature of GCC. Such a finding has the potential to improve early diagnosis and prognosis and helps to identify new therapeutic targets.