Salt-inducible kinase 1 (SIK1) is induced by gastrin and inhibits migration of gastric adenocarcinoma cells

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 involve...

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Published in:PloS one 2014-11, Vol.9 (11), p.e112485-e112485
Main Authors: Selvik, Linn-Karina M, Rao, Shalini, Steigedal, Tonje S, Haltbakk, Ildri, Misund, Kristine, Bruland, Torunn, Prestvik, Wenche S, Lægreid, Astrid, Thommesen, Liv
Format: Article
Language:English
Subjects:
Activator protein 1
Adenocarcinoma
Adenocarcinoma - genetics
Adenocarcinoma - metabolism
Adenocarcinoma - pathology
AMP
AMP-activated protein kinase
Animals
Apoptosis
Biology and Life Sciences
Breast cancer
c-Fos protein
Cell growth
Cell Line, Tumor
Cell migration
Cell Movement - drug effects
Cholecystokinin
Cyclic AMP Response Element Modulator - metabolism
Ectopic expression
Gastric cancer
Gastrin
Gastrins - pharmacology
Gene expression
Histone deacetylase
Hormones - pharmacology
Humans
Invasiveness
Kinases
Liver
LKB1 protein
Luciferase
Medical research
Medicine
Medicine and Health Sciences
Metabolism
Metastases
Metastasis
Molecular modelling
NF-κB protein
Nuclear transport
Penicillin
Phosphorylation
Phosphotransferases
Plasmids
Protein-Serine-Threonine Kinases - genetics
Protein-Serine-Threonine Kinases - metabolism
Proteins
Rats
Rodents
Salt-inducible kinase
Salts
Science
Signal Transduction - drug effects
Signaling
siRNA
Stomach cancer
Stomach Neoplasms - genetics
Stomach Neoplasms - metabolism
Stomach Neoplasms - pathology
Transcription factors
Tumor cell lines
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0112485