Both Wnt and mTOR signaling pathways are involved in insulin-stimulated proto-oncogene expression in intestinal cells.
Subjects with Type II diabetes mellitus are more vulnerable in developing colorectal tumors, suggesting that hyperinsulinemia may stimulate proto-oncogene expression, and the existence of crosstalk between insulin signaling and pathways that are involved in colorectal tumor formation. We show here that insulin stimulates cell proliferation and c-Myc expression in colon cancer cell lines HT29 and Caco-2, intestinal non-cancer cell line IEC-6, and primary fetal rat intestinal cell (FRIC) cultures. The effect of insulin was blocked by phosphoinositide-3 Kinase (PI3K) inhibition, but only partially attenuated by inhibition of Protein kinase B (PKB), indicating the existence of both PKB-dependent and -independent mechanisms. The PKB-dependent mechanism of insulin-stimulated c-Myc expression in HT29 cells was shown to involve the activation of mTOR in c-Myc translation. In the investigation of the PKB-independent mechanism, we found that insulin-induced nuclear translocation of beta-catenin (beta-cat), an effector of Wnt signaling. Furthermore, insulin stimulated the expression of TopFlash, a Wnt-responsive reporter gene. Finally, chromatin immunoprecipitation (ChIP) detected significant increases in the binding of beta-cat to two TCF binding sites of the human c-Myc promoter following insulin treatment. Our observations support the existence of crosstalk between insulin and Wnt signaling pathways, and suggest that the crosstalk involves a PKB-independent mechanism.
Sun
Jane
J
Division of Cell and Molecular Biology, University Health Network, Canada.
Jin
Tianru
T
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D006946:Hyperinsulinism / Q000378:metabolism; D007328:Insulin / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000166:cytology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
D007328:Insulin; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D000090063:Proto-Oncogene Mas; D051057:Proto-Oncogene Proteins c-akt; D016271:Proto-Oncogene Proteins c-myc; D058570:TOR Serine-Threonine Kinases; D051153:Wnt Proteins; D051176:beta Catenin; C000715470:MAS1 protein, human; C546842:MTOR protein, human; C546845:mTOR protein, rat