Oncogenic Ras differentially regulates metabolism and anoikis in extracellular matrix-detached cells
| Autor: | Cassandra L. Buchheit, Sienna M. Durbin, Daniel J. Pape, Chelsea McCallister, C A Davison-Versagli, Siyuan Zhang, Joshua A. Mason, Zachary T. Schafer, Amy K. Leliaert, J Zuo |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Programmed cell death Down-Regulation Protein Serine-Threonine Kinases Biology p38 Mitogen-Activated Protein Kinases Immediate-Early Proteins Phosphatidylinositol 3-Kinases 03 medical and health sciences Adenosine Triphosphate Cell Line Tumor Phosphoprotein Phosphatases Humans Anoikis RNA Small Interfering Molecular Biology Protein kinase B Caspase 7 Original Paper Caspase 3 Cell growth Effector Nuclear Proteins Cell Biology HCT116 Cells Extracellular Matrix Cell biology Glucose Hydrazines 030104 developmental biology Cell culture Benzamides Cancer cell ras Proteins RNA Interference Signal transduction Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | Cell Death & Differentiation. 23:1271-1282 |
| ISSN: | 1476-5403 1350-9047 |
| DOI: | 10.1038/cdd.2016.15 |
| Popis: | In order for cancer cells to survive during metastasis, they must overcome anoikis, a caspase-dependent cell death process triggered by extracellular matrix (ECM) detachment, and rectify detachment-induced metabolic defects that compromise cell survival. However, the precise signals used by cancer cells to facilitate their survival during metastasis remain poorly understood. We have discovered that oncogenic Ras facilitates the survival of ECM-detached cancer cells by using distinct effector pathways to regulate metabolism and block anoikis. Surprisingly, we find that while Ras-mediated phosphatidylinositol (3)-kinase signaling is critical for rectifying ECM-detachment-induced metabolic deficiencies, the critical downstream effector is serum and glucocorticoid-regulated kinase-1 (SGK-1) rather than Akt. Our data also indicate that oncogenic Ras blocks anoikis by diminishing expression of the phosphatase PHLPP1 (PH Domain and Leucine-Rich Repeat Protein Phosphatase 1), which promotes anoikis through the activation of p38 MAPK. Thus, our study represents a novel paradigm whereby oncogene-initiated signal transduction can promote the survival of ECM-detached cells through divergent downstream effectors. |
| Databáze: | OpenAIRE |
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