Constitutively active Akt-mediated cellular senescence inhibits apoptosis in adenocarcinoma of the esophagogastric junction

Abstract

The mechanisms of initiation and progression of adenocarcinoma of the esophagogastric junction (AEG) are largely unclear. To elucidate such mechanisms, we looked for correlations between histopathological and immunohistochemical features of Siewert type II AEG cases and gastric non-cardia carcinoma (GNCC) cases and AEG clinicopathological data. MKN74 gastric cancer cells stably overexpressing active Akt (myr-Akt), inactive Akt (MAA-Akt), and mutant (mt) β-catenin (mt-β-cat) were also used. Overall survival but not disease-free survival was worse for AEG compared to GNCC. This correlated with significantly lower cleaved PARP1 scores, less apoptotic figures, and higher levels of phospho (p) Akt, pGSK-3β, and nuclear β-catenin. myr-Akt cells exhibited senescence-like features, along with increased mouse double minute-2 (MDM2) expression and p53-independent stabilization of p21^waf1; this was consistent with the high p21^waf1 score and frequent mutant (mt) p53 status in AEG as compared to GNCC. Moreover, myr-Akt cells treated with cisplatin (CDDP) displayed less apoptotic features and had a high BCL2:BAX ratio; the converse was observed in MAA-Akt cells. Finally, mt-β-cat cells exhibited senescent features and were sensitive to CDDP-induced apoptosis, independently of Akt and GSK-3β status. In conclusion, constitutively active Akt induces cellular senescence through p53-independent stabilization of p21^waf1, which leads to sustained high BCL2 expression and protects against apoptosis. Together with the GSK-3β/β-catenin axis and high MDM2 expression, this contributes to AEG progression.