Effects of insulin and pathway inhibitors on the PI3K-Akt- mTOR phosphorylation profile in acute myeloid leukemia cells

作     者：Ina Nepstad Kimberley Joanne Hatfield Ida Sofie Grønningsæter Elise Aasebø Maria Hernandez-Valladares Karen Marie Hagen Kristin Paulsen Rye Frode SBerven Frode Selheim Håkon Reikvam Øystein Bruserud 

作者机构：Section for HematologyDepartment of Clinical ScienceUniversity of BergenBergenNorway Department of Immunology and Transfusion MedicineHaukeland University HospitalBergenNorway Department of BiomedicineFaculty of Medicine and DentistryUniversity of BergenJonas Lies vei 915009 BergenNorway Section for HematologyDepartment of MedicineHaukeland University HospitalBergenNorway 

出 版 物：《Signal Transduction and Targeted Therapy》 (信号转导与靶向治疗（英文）)

年 卷 期：2019年第4卷第1期

页      面：504-515页

核心收录：

学科分类：0710[理学-生物学] 1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 100214[医学-肿瘤学] 10[医学] 

基　　金：The studies received financial support from the Norwegian Cancer Society the University of Bergen and Helse-Vest 

主　　题：metabolism myeloid mTOR 

摘      要：The phosphatidylinositol 3-kinase(PI3K)-Akt-mechanistic target of rapamycin(mTOR)pathway is constitutively activated in human acute myeloid leukemia(AML)cells and is regarded as a possible therapeutic *** is an agonist of this pathway and a growth factor for AML *** characterized the effect of insulin on the phosphorylation of 10 mediators in the main track of the PI3K-Akt-mTOR pathway in AML cells from 76 consecutive *** overall results showed that insulin significantly increased the phosphorylation of all investigated ***,insulin effects on the pathway activation profile varied among patients,and increased phosphorylation in all mediators was observed only in a minority of patients;in other patients,insulin had divergent *** gene expression profiling and proteomic/phosphoproteomic comparisons suggested that AML cells from these two patient subsets differed with regard to AML cell differentiation,transcriptional regulation,RNA metabolism,and cellular *** insulin-induced phosphorylation was associated with weakened antiproliferative effects of metabolic ***3K,Akt,and mTOR inhibitors also caused divergent effects on the overall pathway phosphorylation profile in the presence of insulin,although PI3K and Akt inhibition caused a general reduction in Akt pT308 and 4EBP1 pT36/pT45 *** Akt inhibition,the phosphorylation of upstream mediators was generally increased or *** contrast,mTOR inhibition reduced mTOR pS2448 and S6 pS244 phosphorylation but increased Akt pT308 *** conclusion,the effects of both insulin and PI3K-Akt-mTOR inhibitors differ between AML patient subsets,and differences in insulin responsiveness are associated with differential susceptibility to metabolic targeting.