Activation of Akt is increased in the dysplasia-carcinoma sequence in Barrett's oesophagus and contributes to increased proliferation and inhibition of apoptosis: a histopathological and functional study

Abstract

BackgroundThe incidence of oesophageal adenocarcinoma is increasing rapidly in the developed world. The serine-threonine protein kinase and proto-oncogene Akt has been reported to regulate proliferation and apoptosis in several tissues but there are no data on the involvement of Akt in oesophageal carcinogenesis. Therefore we have examined the activation of Akt in Barrett's oesophagus and oesophageal adenocarcinoma and the functional effects of Akt activation in vitro.MethodsExpression of total and active (phosphorylated) Akt were determined in endoscopic biopsies and surgical resection specimens using immunohistochemistry. The functional effects of Akt were examined using Barrett's adenocarcinoma cells in culture.ResultsIn normal squamous oesophagus, erosive oesophagitis and non-dysplastic Barrett's oesophagus, phospho-Akt was limited to the basal 1/3 of the mucosa. Image analysis confirmed that Akt activation was significantly increased in non-dysplastic Barrett's oesophagus compared to squamous epithelium and further significantly increased in high-grade dysplasia and adenocarcinoma. In all cases of high grade dysplasia and adenocarcinoma Akt was activated in the luminal 1/3 of the epithelium. Transient acid exposure and the obesity hormone leptin activated Akt, stimulated proliferation and inhibited apoptosis: the combination of acid and leptin was synergistic. Inhibition of Akt phosphorylation with LY294002 increased apoptosis and blocked the effects of acid and leptin both alone and in combination. Activation of Akt was associated with downstream phosphorylation and deactivation of the pro-apoptotic protein Bad and phosphorylation of the Forkhead family transcription factor FOXO1.ConclusionAkt is abnormally activated in Barrett's oesophagus, high grade dysplasia and adenocarcinoma. Akt activation promotes proliferation and inhibits apoptosis in Barrett's adenocarcinoma cells and both transient acid exposure and leptin stimulate Akt phosphorylation. Downstream targets of Akt include Bad and Forkhead transcription factors. Activation of Akt in obesity and by reflux of gastric acid may be important in the pathogenesis of Barrett's adenocarcinoma

Procyanidin effects on oesophageal adenocarcinoma cells strongly depend on flavan‐3‐ol degree of polymerization

“…Although this requires further investigations, these results raise the possibility that one or more signalling cascades becomes increasingly disrupted during cancer progression [36,37], resulting in a reduced sensitivity to PA exposure. Data presented here demonstrate for the first time that procyanidins can alter the cell cycle and induce apoptosis in oesophageal cancer cells, with a direct correlation between the magnitude of the effect and the degree of polymerization of the flavan-3-ols applied, and suggesting a mechanism whereby polymeric PA may have the potential to affect the development of OA.…”

Sorafenib Triggers Antiproliferative and Pro-Apoptotic Signals in Human Esophageal Adenocarcinoma Cells

“…Moreover, constituents of gastroesophageal refluxate, i.e., acid and bile acids modulate Barrett's cell proliferation and apoptosis increasing substantially the risk for EA [17,19]. We and others have previously pointed out the role of acid and bile acids to increase cell proliferation and survival in Barrett's cell line by up-regulating MAPK and PI3k/Akt signals [20][21][22][23][24][25][26][27]. The concomitant inductions of cyclin D1 and cyclin E in response to theses agents drive cell cycle progression through G1 to S transition [28][29][30].…”

AKT plays a crucial role in gastric cancer

“…In vitro analysis has revealed that only CGA and MKN28 cancer cells demonstrated upregulation of pAKT in response to brief NO exposure. In Barrett's esophagus, activation of AKT is associated with dysplasia-carcinoma sequence (39). In addition, only CGA has been found to express hTERT (13).…”