Abstract
Salt-inducible kinase 1 (SIK1/Snf1lk) belongs to the AMP-activated protein kinase (AMPK) family of kinases, all of which play major roles in regulating metabolism and cell growth. Recent studies have shown that reduced levels of SIK1 are associated with poor outcome in cancers, and that this involves an invasive cellular phenotype with increased metastatic potential. However, the molecular mechanism(s) regulated by SIK1 in cancer cells is not well explored. The peptide hormone gastrin regulates cellular processes involved in oncogenesis, including proliferation, apoptosis, migration and invasion. The aim of this study was to examine the role of SIK1 in gastrin responsive adenocarcinoma cell lines AR42J, AGS-GR and MKN45. We show that gastrin, known to signal through the Gq/G11-coupled CCK2 receptor, induces SIK1 expression in adenocarcinoma cells, and that transcriptional activation of SIK1 is negatively regulated by the Inducible cAMP early repressor (ICER). We demonstrate that gastrin-mediated signalling induces phosphorylation of Liver Kinase 1B (LKB1) Ser-428 and SIK1 Thr-182. Ectopic expression of SIK1 increases gastrin-induced phosphorylation of histone deacetylase 4 (HDAC4) and enhances gastrin-induced transcription of c-fos and CRE-, SRE-, AP1- and NF-κB-driven luciferase reporter plasmids. We also show that gastrin induces phosphorylation and nuclear export of HDACs. Next we find that siRNA mediated knockdown of SIK1 increases migration of the gastric adenocarcinoma cell line AGS-GR. Evidence provided here demonstrates that SIK1 is regulated by gastrin and influences gastrin elicited signalling in gastric adenocarcinoma cells. The results from the present study are relevant for the understanding of molecular mechanisms involved in gastric adenocarcinomas.
Highlights
Gastrin is a regulatory peptide hormone which plays a crucial role in integration of exocrine and endocrine functions in the gastrointestinal tract
In the present study we show that gastrin induces transient Salt-Inducible Kinase 1 (SIK1) expression in pancreatic and gastric adenocarcinoma cells, and that the gastrininduced SIK1 expression is negatively regulated by Inducible cAMP early repressor (ICER)
In the present study we further explored the role of SIK1 in the gastrin responsive cell lines AGS-GR, MKN45 and AR42J
Summary
Gastrin is a regulatory peptide hormone which plays a crucial role in integration of exocrine and endocrine functions in the gastrointestinal tract. By genome wide gene expression profiling we found that gastrin induces transcription of Saltinducible kinase 1 (Sik1/Snf1lk) in the pancreatic adenocarcinoma cell line AR42J [4]. The AMPKs play major roles in regulating metabolism and cell growth [10,11,12]. Clinical studies have shown that reduced levels of SIK1 are associated with distal metastases and poor outcome in breast cancer, and SIK1 expression has been associated with a tumour suppressor function [13,14,15,16]. Cheng and co-authors [16] have demonstrated that SIK1 links the tumour suppressor Liver Kinase 1B (LKB1) to p53-
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