Research Papers:

Helicobacter pylori CagA protein activates Akt and attenuates chemotherapeutics-induced apoptosis in gastric cancer cells

Keng-Hsueh Lan, Wei-Ping Lee, Yu-Shan Wang, Shi-Xian Liao and Keng-Hsin Lan _

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Oncotarget. 2017; 8:113460-113471. https://doi.org/10.18632/oncotarget.23050

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Keng-Hsueh Lan1, Wei-Ping Lee2,7, Yu-Shan Wang3, Shi-Xian Liao4 and Keng-Hsin Lan4,5,6

1Division of Radiation Oncology, Department of Oncology, National Taiwan University Hospital National Taiwan University Cancer Center, Taipei, Taiwan

2Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan

3Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, Hsinchu, Taiwan

4Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

5Department of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan

6Department and Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan

7Department and Institute of Biochemistry, National Yang-Ming University, Taipei, Taiwan

Correspondence to:

Keng-Hsin Lan, email: [email protected]

Keywords: Helicobacter pylori; CagA; Akt; chemotherapeutics

Received: July 21, 2017     Accepted: November 13, 2017     Published: December 09, 2017


Infection with cagA-positive Helicobacter pylori is associated with a higher risk of gastric cancer. The cagA gene product, CagA, is translocated into gastric epithelial cells and perturbs host cellular biological functions. Etoposide, a topoisomerase II inhibitor widely used to couple DNA damage to apoptosis, is a common cytotoxic agent used for advanced gastric cancer. We investigate the effect of CagA on etoposide-induced apoptosis in gastric cancer cells to elucidate whether CagA play a role in gastric carcinogenesis via impairing DNA damage-dependent apoptosis. AGS cell lines stably expressing CagA isolated from H. pylori 26695 strain were established. In the presence of etoposide, viability of parental AGS cells was decreased in a time-and dose-dependent manner, whereas CagA-expressing AGS cells were less susceptible to etoposide induced cell-killing effect. Suppression of etoposide-induced apoptosis was shown in CagA-expressing but not in parental AGS cells by DNA fragmentation, cell cycle, and annexin-V assays. This inhibitory effect of etoposide-induced apoptosis conferred by CagA was also demonstrated in SCM1 and MKN45 gastric cancer cell lines, with two additional chemotherapeutics, 5-FU and cisplatin. The effect of Akt activation on inhibition of etoposide-induced cytotoxicity by CagA was also evaluated. CagA expression and etoposide administration activate Akt in a dose-dependent manner. Enhancement of etoposide cytotoxicity by a PI-3-kinase inhibitor, LY294002, was evident in parental but was attenuated in CagA-expressing AGS cells. CagA may activate Akt, either in the absence or presence of etoposide, potentially contributing to gastric carcinogenesis associated with H. pylori infection and therapeutic resistance by impairing DNA damage-dependent apoptosis.

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