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Relative resistance of SGK1 knockout mice against chemical carcinogenesis
Omaima Nasir1, Kan Wang, Michael Föller
1Department of Physiology, University of Tuebingen, Germany.
Abstract:
The serum and glucocorticoid inducible kinase SGK1 was originally cloned from mammary tumor cells. SGK1 was found to be up-regulated in a variety of tumors, but down-regulated in several distinct tumors. Thus, evidence for a role of SGK1 in tumor growth remained conflicting. According to in vitro observations, SGK1 is up-regulated by the oncogene beta-catenin and negatively regulates the proapoptotic transcription factor FOXO3a, which in turn stimulates transcription of the Bcl2-interacting mediator BIM. This study aimed to define the role of SGK1 in colon carcinoma in vivo. SGK1 knockout mice (sgk1(-/-)) and their wild type littermates (sgk1(+/+)) were subjected to chemical cancerogenesis (intraperitoneal injection of 20 mg/kg 1,2-dimethylhydrazine followed by three cycles of 30 g/L synthetic dextran sulfate sodium for 7 days). Moreover, SGK1 was silenced in HEK293 cells. FOXO3a and BIM protein abundance was determined by Western blotting and immunohistochemistry. Following chemical cancerogenesis, sgk1(-/-)mice developed significantly less colonic tumors than sgk1(+/+)mice. According to Western blotting and immunohistochemistry, SGK1 deficiency enhanced the expression of FOXO3a and BIM both, in vitro and in vivo. SGK1 deficiency counteracts the development of colonic tumors, an effect at least in part due to up-regulation of FOXO3a and BIM.
Insights
Serum and glucocorticoid inducible kinase (SGK1) deficiency reduces colon tumor development in mice. This effect is linked to increased expression of FOXO3a and BIM, key regulators of apoptosis.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Serum and glucocorticoid inducible kinase (SGK1) has a complex role in tumorigenesis, with conflicting reports on its up-regulation or down-regulation in various cancers.
- In vitro studies suggest SGK1 promotes tumor growth by inhibiting the pro-apoptotic transcription factor FOXO3a, which normally up-regulates BIM.
Purpose of the Study:
- To investigate the in vivo role of SGK1 in colon carcinoma development.
- To determine the impact of SGK1 deficiency on FOXO3a and BIM protein levels in the context of colon cancer.
Main Methods:
- Utilized SGK1 knockout mice and wild-type littermates subjected to chemical carcinogenesis.
- Employed HEK293 cells for in vitro SGK1 silencing experiments.
- Assessed protein expression of FOXO3a and BIM using Western blotting and immunohistochemistry.
Main Results:
- SGK1 knockout mice exhibited significantly fewer colonic tumors compared to wild-type controls after chemical carcinogenesis.
- SGK1 deficiency led to enhanced expression of both FOXO3a and BIM proteins, observed both in vitro and in vivo.
- These findings indicate that SGK1 plays a pro-tumorigenic role in colon cancer.
Conclusions:
- SGK1 deficiency counteracts colon tumor development.
- The tumor-suppressive effect of SGK1 deficiency is, at least partly, mediated by the upregulation of FOXO3a and BIM.
- Targeting SGK1 could be a potential therapeutic strategy for colon carcinoma.
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