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

Abstract

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.

Metformin attenuates synergic effect of diabetes mellitus and Helicobacter pylori infection on gastric cancer cells proliferation by suppressing PTEN expression

“…47,48 Previous results presented that etoposide boosted the phosphorylation of Akt while minimizing cell survival via the induction of GC apoptosis. 49 It was shown that the abnormal methylation in PTEN promoter was substantially reduced in Uyghur subjects suffering from mild cases of T2DM. It was further shown that the hypomethylation in PTEN promoter was pretty common in T2DM subjects, indicating that PTEN might contribute to T2DM pathogenesis among Uyghur people.…”

<p><em>Helicobacter pylori</em> CagA Protein Attenuates 5-Fu Sensitivity of Gastric Cancer Cells Through Upregulating Cellular Glucose Metabolism</p>

“…Recently studies illustrated the Helicobacter pylori CagA protein activates Akt pathway and desensitizes etoposide, another cytotoxic agent for treatment of advanced gastric cancer, 22 indicating CagA promotes glycolysis could through activation of Akt. To further investigate the underlying molecular mechanism of the CagA-promoted glucose metabolism, we examined Akt pathway in CagA positive gastric cancer cells.…”

“…To investigate the molecular mechanisms of the CagA-promoted glycolysis, we examined the phosphorylation of Akt since it has been reported that activation of Akt pathway contributed to the glycolysis upregulation. 22 Expectedly, overexpression of CagA promoted the phosphorylation of Akt. Thus, we treated gastric cancer cells with Akt inhibitor and found inhibition of Akt significantly blocked the CagA-upregulated cellular glycolysis, suggesting blocking glycolysis by either Akt inhibitor or glycolysis inhibitor could enhance the cytotoxicity of 5-Fu.…”

Bacterial-Viral Interactions in Human Orodigestive and Female Genital Tract Cancers: A Summary of Epidemiologic and Laboratory Evidence

“…Specifically, activation of PI3K/AKT and ERK/JNK pathways, which leads to increased cell growth and survival and induction EMT as well as increased cell motility, respectively [ 60 , 146 ], has been observed in both EBV- and H. pylori -associated GC. In case of EBV, its oncoprotein LMP2A is responsible for these activations, which has been confirmed in both in vitro and in an in vivo transgenic mouse model [ 146 , 154 , 155 , 156 ], while CagA is the primary virulence factor of H. pylori that activates these pathways [ 142 , 146 , 157 , 158 , 159 , 160 ].…”