Gastric cancer (GC) is one of the most
malignancies leading to human mortality due to its development, progress,
metastasis and poor prognosis, despite the development of remarkable
chemotherapy and surgery. The 5-fluorouracil (5-Fu) is an effective anti-
gastric cancer agent. However, a fraction of GC patients acquire
5-Fu chemoresistance.
METHODS: In this study, the CagA
protein was detected from CagA-positive
gastric cancer patients by qRT-PCR and immunohistochemistry. The
5-Fu resistant
gastric cancer cell line was generated from MKN45-CagA cells which was transfected with CagA overexpression vector. Cellular
glucose metabolism was determined by measurements of
glucose uptake,
lactate product and glycolysis
enzymes.
RESULTS: We report that the Helicobacter pylori (H. pylori)-secreted
Cytotoxin-associated gene A (CagA)
oncoprotein is positively correlated with
5-Fu resistance of
gastric cancer. From totally 72 CagA-positive
gastric cancer patients, CagA high-expressed patients showed more resistance to
5-Fu than CagA low-expressed patients. Moreover, statistical analysis revealed that CagA
mRNA and
protein expressions were significantly upregulated in
5-Fu resistant
gastric cancer patients. We observed that CagA
protein is upregulated in
5-Fu resistant
gastric cancer cells compared with sensitive cells. Interestingly, cellular
glucose metabolism was upregulated; the
glucose uptake and
lactate production were significantly higher in
5-Fu resistant
gastric cancer cells. The Akt phosphorylation and expressions of glycolysis key
enzymes,
Hexokinase 2 and LDHA, were significantly upregulated in
5-Fu resistant
gastric cancer cells. On the other way, inhibition of glycolysis or Akt pathway effectively overcame
5-Fu resistance from both in vitro and in vivo models. Finally, we report that the combination of Akt or glycolysis inhibitor with
5-Fu could synergistically enhance the cytotoxicity of
5-Fu to CagA-overexpressed
gastric cancer cells.
DISCUSSION: