Salt-Inducible Kinase 1 (SIK1) Is Induced by Gastrin and Inhibits Migration of Gastric Adenocarcinoma Cells

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.

Gastrin activates autophagy and increases migration and survival of gastric adenocarcinoma cells

“…The xCELLigence® DP system (Roche Diagnostics GmbH, Germany) was used to study migration as previously described [25]. Briefly, AGS-Gr cells were seeded into (5.0 x 10 4 cells/well) the CIM-Plate 16 (Roche).…”

“…Since the data suggests that gastrin induces autophagy, we asked if this involves the activation of ULK1. We have recently demonstrated that gastrin induces STK11 Ser 428 phosphorylation in AGS-Gr and MKN45 cells [25], indicating that the STK11-PRKAA2-ULK1 signalling pathway might be involved in gastrin mediated induction of autophagy. Thus, we treated cells with gastrin and examined the phosphorylation of PRKAA2 by immunoblotting.…”

Targeting LKB1 in cancer – exposing and exploiting vulnerabilities

“…Reports on the role of NUAK2 in tumours of different origin vary: in melanoma, NUAK2 (SNARK) levels correlate negatively with patient survival ( Namiki et al , 2011 ), whereas in ovarian cancer patients, an opposite trend was reported ( Emmanuel et al , 2011 ). SIK1, SIK2 (QIK) and SIK3 (QSK) have been reported to have a role in metastasis in gastric ADCs ( Selvik et al , 2014 ) and mitotic progression in prostate and ovarian cancers ( Ahmed et al , 2010 ; Chen et al , 2014 ; Bon et al , 2015 ). Additionally, SIK1 was shown to be required for P53-dependent anoikis, and RNAi-mediated gene silencing of SIK1 resulted in increased lung micrometastases in xenografts injected with transformed human mammary epithelial cells.…”

MicroRNA‑373 promotes cell migration via targeting salt‑inducible kinase 1 expression in melanoma

“…In human hepatocellular carcinoma (HCC), SIK1 markedly inhibited EMT, tumor growth and metastasis and provided a potential new candidate for HCC therapy (28). Reduced expression of SIK1 was also identified to be associated with poor outcomes in gastric carcinoma (19). Furthermore, SIK1 could be the potential target for numerous miRs.…”

“…In non-small cell lung cancer, downregulation of SIK1 enhances epithelial-mesenchymal transition (EMT) and radioresistance (18). In addition, induced SIK1 expression has been reported to inhibit gastric cancer cell migration (19). However, the functional role of SIK1 in melanoma remains largely unknown.…”