Prevention of tumour cell apoptosis associated with sustained protein kinase B phosphorylation is more sensitive to regulation by insulin signalling than stimulation of proliferation and extracellular signal-regulated kinase
| Autor: | Claudia Ghirlanda, Markus Niessen, Christoph Schmid |
|---|---|
| Přispěvatelé: | University of Zurich, Schmid, Christoph |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Adolescent Proto-Oncogene Proteins c-akt MAP Kinase Signaling System medicine.medical_treatment Clinical Biochemistry 10265 Clinic for Endocrinology and Diabetology Apoptosis 610 Medicine & health Biology IGF1 Insulin Obesity Osteosarcoma cells PI3K 1308 Clinical Biochemistry Article 1307 Cell Biology 03 medical and health sciences medicine 1312 Molecular Biology Humans Insulin-Like Growth Factor I Phosphorylation Protein kinase B Molecular Biology PI3K/AKT/mTOR pathway Cell Proliferation Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Kinase Akt/PKB signaling pathway Growth factor General Medicine Cell Biology 3. Good health Intracellular signal transduction 030104 developmental biology A549 Cells Cancer research Female |
| Zdroj: | Molecular and Cellular Biochemistry, 432 (1-2) Molecular and Cellular Biochemistry |
| DOI: | 10.5167/uzh-149649 |
| Popis: | Insulin controls blood glucose while insulin-like growth factor (IGF) 1 is an important growth factor. Interestingly, both hormones have overlapping bioactivities and can activate the same intracellular signal transduction cascades. Growth control (mainly by IGF1) and metabolic function (predominantly by insulin) are believed to depend on activation of extracellular signal-regulated kinases (ERKs) 1/2 and protein kinase B (Akt/PKB), respectively. Therefore, insulin analogues that are used to normalize blood glucose are tested for their ability to preferentially activate Akt/PKB but not ERK1/2 and mitogenesis. Growth hormone, IGF1, and hyperinsulinemia are associated with increased risk of growth progression of some cancer types. To test if continuous exposure to insulin can favour tumour growth, we studied insulin/IGF1-dependent activation of ERK1/2 and Akt/PKB by Western blotting, inhibition of apoptosis by ELISA, and induction of proliferation by [3H]-thymidine incorporation in Saos-2/B10 osteosarcoma cells. IGF1 and insulin both induced proliferation and prevented apoptosis effectively. Regulation of apoptosis was far more sensitive than regulation of proliferation. IGF1 and insulin activated PKB (Akt/PKB) rapidly and consistently maintained its phosphorylation. Activation of ERK1/2 was only observed in response to IGF1. Loss of p-Akt/PKB (but not of p-ERK1/2) was associated with increased apoptosis, and protection from apoptosis was lost when activation of Akt/PKB was inhibited. These findings in Saos-2/B10 cells were also replicated in the A549 cell line, originally derived from a human lung carcinoma. Therefore, IGF1 and insulin more likely (at lower concentrations) enhance tumour cell survival than proliferation, via activation and maintenance of phosphatidylinositol 3-kinase activity and p-Akt/PKB. Electronic supplementary material The online version of this article (doi:10.1007/s11010-017-2996-y) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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