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Helicobacter pylori CagA Protein Attenuates 5-Fu Sensitivity of Gastric Cancer Cells Through Upregulating Cellular Glucose Metabolism

Authors Gao S, Song D, Liu Y, Yan H, Chen X

Received 12 September 2019

Accepted for publication 15 May 2020

Published 1 July 2020 Volume 2020:13 Pages 6339—6349


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 3

Editor who approved publication: Prof. Dr. Jianmin Xu

Sujie Gao,1 Defeng Song,2 Yiting Liu,3 Hongwei Yan,4 Xuebo Chen2

1Department of Anesthesia, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, People’s Republic of China 130033; 2Department of General Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province 130033, People’s Republic of China; 3Department of Radiology, Peking University School of Oncology, Beijing Cancer Hospital & Institute, Beijing 100036, People’s Republic of China; 4Department of General Surgery, Chinese Medicine Hospital, Liuhe, Jilin Province 135300, People’s Republic of China

Correspondence: Xuebo Chen
Department of General Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province 130033, People’s Republic of China

Introduction: 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: In summary, our study demonstrated a CagA-Akt-glycolysis-5-Fu resistance axis, contributing to the development of new therapeutic agents against chemoresistant human gastric cancer.

Keywords: aerobic glycolysis, gastric cancer, 5-Fu resistance, CagA, Helicobacter pylori infection, Warburg effect, chemoresistance

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