ABSTRACT
The growth factor receptor/PI3K/AKT pathway is an important drug target in many cancers including Glioblastoma. AKT, a key node in the pathway, has 3 isoforms, AKT1, AKT2 and AKT3. Here we investigate their role in GBM. We find each activated, ser473 phosphorylated isoform is present in some GBMs but expression patterns vary. There is a direct relationship between human GBM patient outcome and both AKT1 and AKT2 mRNA levels, but an inverse relationship with AKT3 mRNA. Furthermore, AKT3 mRNA levels were high in a less aggressive GBM subtype. Overexpressing AKT3 improves survival in a rodent model of GBM and decreases colony forming efficiency, but not growth rate, in glioma cells. Silencing AKT3 slows cell cycle progression in one cell line and increases apoptosis in another. Our studies of AKT3 substrates indicate (1) silencing both AKT2 and AKT3 reduces GSK3 phosphorylation (2) only AKT2 silencing reduces S6 phosphorylation. Since S6 phosphorylation is a marker of mTORC1 activity this indicates that AKT2 activates mTORC1, but AKT3 does not. Our results indicate AKT isoforms have different roles and downstream substrates in GBM. Unexpectedly, they indicate AKT3 delays tumor progression. Therefore strategies that inhibit AKT3 may be unhelpful in some GBM patients.
Subject(s)
Glioblastoma/enzymology , Glioblastoma/genetics , Protein Isoforms/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Cell Cycle/genetics , Cell Line, Tumor , Cell Survival , Female , Gene Expression Regulation, Neoplastic/physiology , Glioblastoma/pathology , Glycogen Synthase Kinase 3/metabolism , Humans , Kaplan-Meier Estimate , Male , Phosphorylation , Protein Isoforms/genetics , Proto-Oncogene Proteins c-akt/genetics , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Serine/metabolism , Signal Transduction/genetics , Time Factors , TransfectionABSTRACT
Nitrate and perchlorate salts of 2,4,6-trimethylaniline have been prepared and characterized by X-ray crystallography and gravimetric analyses. Their thermal decomposition has been studied by TG, TG-DSC and ignition/explosion delays. It has been observed that proton transfer from substituted anilinium ion to nitrate and perchlorate ion regenerate amine, HNO(3) and HClO(4) in condensed phase at higher temperature, where oxidation-reduction between amine and acids leads to ignition and explosion. The kinetics of thermal decomposition was evaluated by applying model fitting as well as isoconversional methods. The values of calculated activation energy of nitrate and perchlorate salts are 77.9 and 118.2 kJ mol(-1) respectively. The possible pathways of thermolysis of these salts have also been proposed.
