Colorectal carcinoma cells--regulation of survival and growth by SGK1.
Colorectal carcinoma is among the most common malignancies. The tumour cells may arise from mutations in genes encoding proteins involved in the regulation of cell survival and proliferation. Recent evidence disclosed the sensitivity of colon carcinoma to the expression of ubiquitous serum and glucocorticoid inducible kinase-1 (SGK1). The kinase is activated by insulin and growth factors via the phosphatidylinositide-3-kinase (PI3K) and the 3-phosphoinositide dependent kinase (PDK1). SGK1 regulates channels, carriers and Na(+)/K(+)-ATPase, enzymes such as glycogen-synthase-kinase-3 (GSK3) and ubiquitin-ligase Nedd4-2, as well as several transcription factors. SGK1 regulates transport, hormone release, neuroexcitability, inflammation, cell proliferation and apoptosis. SGK1 contributes to metabolic syndrome and the pathophysiology of neurodegeneration, allergy, peptic ulcer, fibrosing disease and response to ischemia. SGK1 is upregulated in some tumours but downregulated in others. SGK1-sensitive mechanisms fostering tumour growth include activation of K(+) channels and Ca(2+) channels, Na(+)/H(+) exchanger, amino acid transporters and glucose transporters, upregulation of the nuclear factor NFkappaB and beta-catenin as well as downregulation of the transcription factors Foxo3a/FKHRL1 and p53. SGK1 enhances survival, invasiveness, motility, epithelial to mesenchymal transition and adhesiveness of tumour cells. Following deficiency of APC (adenoma polyposis coli) or chemical cancerogenesis, SGK1 knockout mice develop less intestinal tumours than their wild-type littermates and pharmacological SGK1 inhibition counteracts growth of prostate cancer cells.
Lang
Florian
F
Department of Physiology, University of Tuebingen, Tübingen, Germany. florian.lang@uni-tuebingen.de
Perrotti
Nicola
N
Stournaras
Christos
C
D000818:Animals; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D002471:Cell Transformation, Neoplastic; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation; D000099184:Serum-Glucocorticoid Regulated Kinases
D004791:Enzyme Inhibitors; D017874:Immediate-Early Proteins; D017346:Protein Serine-Threonine Kinases; D000099184:Serum-Glucocorticoid Regulated Kinases