Serum- and Glucocorticoid-induced Kinase Sgk1 Directly Promotes the Differentiation of Colorectal Cancer Cells and Restrains Metastasis

Abstract

Background and Aims The molecular events that determine intestinal cell differentiation are poorly understood and it is unclear whether it is primarily a passive event or an active process. It is clinically important to gain a greater understanding of the process, since in colorectal cancer (CRC), the degree of differentiation of a tumour is associated with patient survival. SGK1 has previously been identified as a gene that is principally expressed in differentiated intestinal cells. In colorectal cancer (CRC), there is marked downregulation of SGK1 compared to normal tissue. Methods An inducible SGK1 viral overexpression system was utilised to induce re-expression of SGK1 in CRC cell lines. Transcriptomic and phenotypic analyses of these CRC lines was performed and validation in mouse and human cohorts was performed. Results We demonstrate that SGK1 is upregulated in response to, and an important controller of, intestinal cell differentiation. Re-expression of SGK1 in CRC cell lines results in features of differentiation, decreased migration rates, and inhibition of metastasis in an orthotopic xenograft model. These effects may be mediated in part by SGK1-induced PKP3 expression and increased degradation of MYC. Conclusions Our results suggest that SGK1 is an important mediator of differentiation of colorectal cells and may inhibit CRC metastasis.

Glucocorticoid receptor and serum‐ and glucocorticoid‐induced kinase‐1 in esophageal adenocarcinoma and adjacent Barrett's esophagus

“…The results of the present study illustrated that low Sgk1 expression in EAC tumor cells was associated with adverse clinical outcomes. The result was in line with previous findings that showed that low Sgk1 activation predicted poor prognosis of colon cancer patients 19 . The possible mechanism was proposed to be decreased cellular dedifferentiation and migration via PIPK3 expression, which could regulate inflammatory response 19 …”

“…GR downregulation in epithelial cells induces the expression of various proinflammatory genes, including those encoding cytokines and adhesion molecules 12 . It has also been reported that activation of GR and Sgk1 in carcinoma cells inhibits the expression of various proinflammatory genes and suppresses cancer progression 17‐19 . In vitro and in vivo studies have shown that GR activation in urinary bladder carcinoma cells suppresses tumor invasion and metastasis by decreasing cell migration and invasion via matrix metalloproteinase (MMP)‐2/MMP‐9 and interleukin (IL)‐6 downregulation 17 .…”

“…In prostate cancer, GCs inhibit cancer‐associated angiogenesis via vascular endothelial growth factor and IL‐8 downregulation 18 . Sgk1 also reportedly decreased the migration of colon carcinoma cells via Plakophilin‐3 (PIPK3) expression and MYC degradation 19 …”

The Enigmatic Role of Serum & Glucocorticoid Inducible Kinase 1 in the Endometrium

“…Waldegger et al, 1997;Lee et al, 2012;Lang and Stournaras, 2013;Lang et al, 2018 Signaling of SGK1 activation PI-3 kinase-sensitive 3-phosphoinositide (PIP3)-dependent kinases PDK1 and PDK2, Na + /H + exchanger regulating factor 2 (NHERF2), WNK1 (lysine deficient protein kinase 1), mammalian target of rapamycin mTOR complex-2 (mTORC2) composed of mTOR, Rictor (rapamycin-insensitive companion of mTOR), Sin1 (stress-activated protein kinase-interacting protein 1), mLST8 and Protor-1, p38α MAPK, ERK5, cAMP, Ca 2+ -sensitive calmodulin-dependent protein kinase kinase (CaMKK), G-protein Rac1 Waldegger et al, 1997;Lang et al, 2006;Dibble et al, 2009;Peterson et al, 2009;Rosner et al, 2009;Heise et al, 2010;Lyo et al, 2010;Treins et al, 2010;Pearce et al, 2011;Fang et al, 2012;Hall et al, 2012;Na et al, 2013;Thomanetz et al, 2013;Domhan et al, 2014;Tsai et al, 2014;Lang et al, 2018. Heise et al, 2010;Schmidt et al, 2014;Lee et al, 2019). In agreement, SGK1 overexpression can confer resistance of cancer cells to chemotherapy and radiation (Sommer et al, 2013;Talarico et al, 2016).…”

The prospect of serum and glucocorticoid-inducible kinase 1 (SGK1) in cancer therapy: a rising star

“… 1 , 3 , 14 , 15 SGK1 has been previously reported in hypertension, diabetes, hypercoagulability, and autoimmune disease. 5 , 16 , 17 A growing number of recent studies reveal a role for SGK1 in human tumors such as glioblastoma, 18 – 20 breast, 21 – 25 colorectal, 26 – 28 prostate, 29 – 31 thyroid, 32 ovarian, 33 myeloma, 11 and non-small cell lung cancer 34 ( Figure 1 ).…”