Abstract
BackgroundThe peptide hormone gastrin exerts a growth-promoting effect in both normal and malignant gastrointestinal tissue. Gastrin mediates its effect via the cholecystokinin 2 receptor (CCKBR/CCK2R). Although a substantial part of the gastric adenocarcinomas express gastrin and CCKBR, the role of gastrin in tumor development is not completely understood. Autophagy has been implicated in mechanisms governing cytoprotection, tumor growth, and contributes to chemoresistance. This study explores the role of autophagy in response to gastrin in gastric adenocarcinoma cell lines.MethodsImmunoblotting, survival assays and the xCELLigence system were used to study gastrin induced autophagy. Chemical inhibitors of autophagy were utilized to assess the role of this process in the regulation of cellular responses induced by gastrin. Further, knockdown studies using siRNA and immunoblotting were performed to explore the signaling pathways that activate autophagy in response to gastrin treatment.ResultsWe demonstrate that gastrin increases the expression of the autophagy markers MAP1LC3B-II and SQSTM1 in gastric adenocarcinoma cells. Gastrin induces autophagy via activation of the STK11-PRKAA2-ULK1 and that this signaling pathway is involved in increased migration and cell survival. Furthermore, gastrin mediated increase in survival of cells treated with cisplatin is partially dependent on induced autophagy.ConclusionThis study reveals a novel role of gastrin in the regulation of autophagy. It also opens up new avenues in the treatment of gastric cancer by targeting CCKBR mediated signaling and/or autophagy in combination with conventional cytostatic drugs.
Highlights
The peptide hormone gastrin exerts a growth-promoting effect in both normal and malignant gastrointestinal tissue
Gastrin induces autophagy in gastric adenocarcinoma cells Our transcriptome analysis of differentially expressed genes in the pancreatic adenocarcinoma AR42J cells revealed that gastrin upregulates the mRNA level of autophagy related genes (e.g. Sqstm1 and beclin 1 (E-MTAB-1268 and GSE32869)) [22], suggesting that gastrin may induce autophagy
In the AGS-Gr cells treated with gastrin + Bafilomycin A1 (BafA1), we found a significant increase in MAP1LC3B-II and SQSTM1 levels compared to the level in cells treated with BafA1 alone (Fig. 1e; Additional file 1: Figure S2 (a) & (b))
Summary
The peptide hormone gastrin exerts a growth-promoting effect in both normal and malignant gastrointestinal tissue. This study explores the role of autophagy in response to gastrin in gastric adenocarcinoma cell lines. The process of macroautophagy ( referred to as autophagy) involves the engulfment of cytoplasmic material into de novo generated double membrane vesicle called autophagosomes. Microtubule-associated protein 1 light chain 3 beta (MAP1LC3B-I/II/ LC3B) is lipidated when autophagy is induced and plays an essential role in the autophagosome formation [5]. Sequestosome 1 (SQSTM1/p62) facilitates the degradation of polyubiquitinated substrates by autophagy via the direct interaction with ubiquitinated proteins and MAP1LC3B located on the autophagosomal membrane [6]. MAP1LC3B and SQSTM1 are both produced and degraded in a coordinated manner during autophagy and are used as markers to study this process [7, 8]
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