Abstract
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.
MeSH terms
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Adenosine Triphosphate / metabolism
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Anoikis / drug effects
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Benzamides / pharmacology
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Caspase 3 / metabolism
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Caspase 7 / metabolism
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Cell Line, Tumor
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Down-Regulation / drug effects
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Extracellular Matrix / metabolism*
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Glucose / metabolism
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HCT116 Cells
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Humans
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Hydrazines / pharmacology
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Immediate-Early Proteins / antagonists & inhibitors
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Immediate-Early Proteins / genetics
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Immediate-Early Proteins / metabolism
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Nuclear Proteins / antagonists & inhibitors
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoprotein Phosphatases / antagonists & inhibitors
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Phosphoprotein Phosphatases / genetics
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Phosphoprotein Phosphatases / metabolism
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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RNA Interference
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RNA, Small Interfering / metabolism
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Signal Transduction / drug effects
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p38 Mitogen-Activated Protein Kinases / metabolism
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ras Proteins / antagonists & inhibitors
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ras Proteins / genetics
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ras Proteins / metabolism*
Substances
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Benzamides
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EMD 638683
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Hydrazines
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Immediate-Early Proteins
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Nuclear Proteins
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RNA, Small Interfering
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Adenosine Triphosphate
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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serum-glucocorticoid regulated kinase
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p38 Mitogen-Activated Protein Kinases
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PHLPP1 protein, human
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Phosphoprotein Phosphatases
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Caspase 3
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Caspase 7
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ras Proteins
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Glucose