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.
Subject(s)
Extracellular Matrix/metabolism , ras Proteins/metabolism , Adenosine Triphosphate/metabolism , Anoikis/drug effects , Benzamides/pharmacology , Caspase 3/metabolism , Caspase 7/metabolism , Cell Line, Tumor , Down-Regulation/drug effects , Glucose/metabolism , HCT116 Cells , Humans , Hydrazines/pharmacology , Immediate-Early Proteins/antagonists & inhibitors , Immediate-Early Proteins/genetics , Immediate-Early Proteins/metabolism , Nuclear Proteins/antagonists & inhibitors , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Phosphoprotein Phosphatases/antagonists & inhibitors , Phosphoprotein Phosphatases/genetics , Phosphoprotein Phosphatases/metabolism , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , RNA Interference , RNA, Small Interfering/metabolism , Signal Transduction/drug effects , p38 Mitogen-Activated Protein Kinases/metabolism , ras Proteins/antagonists & inhibitors , ras Proteins/geneticsABSTRACT
Data concerning self-reported driving after drinking or using other drugs were collected from 3,382 junior and senior high school students in rural central and southern Illinois. Drinking, drug use, and driving increased steadily with age, with 42% of the 12th grade class indicating they had driven a car at least one time in the past six months after drinking or using other drugs. Riding with a driver who had been drinking also increased with age; 20% of the seventh grade sample had ridden in a car with a drinking driver, while 58% of the 12th grade sample reported having done so. Slightly more females had ridden in a car with a driver who had been drinking than males, while males reported higher rates of driving after drinking or using other drugs than females. Correlation analyses indicated 22 variables related significantly to drinking, drug use, and driving. Forward stepwise multiple regression analysis showed that 11 variables related significantly to riding as a passenger with a drinking driver. Thirteen variables were related significantly to driving after drinking or using other drugs. Frequency of alcohol use variables were the most powerful indicators of self-reported driving after drinking or using other drugs in this sample.
