RRC ID 44754
Author Kurosu T, Nagao T, Wu N, Oshikawa G, Miura O.
Title Inhibition of the PI3K/Akt/GSK3 pathway downstream of BCR/ABL, Jak2-V617F, or FLT3-ITD downregulates DNA damage-induced Chk1 activation as well as G2/M arrest and prominently enhances induction of apoptosis.
Journal PLoS One
Abstract Constitutively-activated tyrosine kinase mutants, such as BCR/ABL, FLT3-ITD, and Jak2-V617F, play important roles in pathogenesis of hematopoietic malignancies and in acquisition of therapy resistance. We previously found that hematopoietic cytokines enhance activation of the checkpoint kinase Chk1 in DNA-damaged hematopoietic cells by inactivating GSK3 through the PI3K/Akt signaling pathway to inhibit apoptosis. Here we examine the possibility that the kinase mutants may also protect DNA-damaged cells by enhancing Chk1 activation. In cells expressing BCR/ABL, FLT3-ITD, or Jak2-V617F, etoposide induced a sustained activation of Chk1, thus leading to the G2/M arrest of cells. Inhibition of these kinases by their inhibitors, imatinib, sorafenib, or JakI-1, significantly abbreviated Chk1 activation, and drastically enhanced apoptosis induced by etoposide. The PI3K inhibitor GD-0941 or the Akt inhibitor MK-2206 showed similar effects with imatinib on etoposide-treated BCR/ABL-expressing cells, including those expressing the imatinib-resistant T315I mutant, while expression of the constitutively activated Akt1-myr mutant conferred resistance to the combined treatment of etoposide and imatinib. GSK3 inhibitors, including LiCl and SB216763, restored the sustained Chk1 activation and mitigated apoptosis in cells treated with etoposide and the inhibitors for aberrant kinases, PI3K, or Akt. These observations raise a possilibity that the aberrant kinases BCR/ABL, FLT3-ITD, and Jak2-V617F may prevent apoptosis induced by DNA-damaging chemotherapeutics, at least partly through enhancement of the Chk1-mediated G2/M checkpoint activation, by inactivating GSK3 through the PI3K/Akt signaling pathway. These results shed light on the molecular mechanisms for chemoresistance of hematological malignancies and provide a rationale for the combined treatment with chemotherapy and the tyrosine kinase or PI3K/Akt pathway inhibitors against these diseases.
Volume 8(11)
Pages e79478
Published 2013
DOI 10.1371/journal.pone.0079478
PII PONE-D-13-23810
PMID 24260231
PMC PMC3832535
MeSH Animals Apoptosis / drug effects Benzamides / pharmacology Cell Cycle / drug effects Cell Line Etoposide / pharmacology Flow Cytometry Fusion Proteins, bcr-abl / genetics Fusion Proteins, bcr-abl / metabolism* Glycogen Synthase Kinase 3 / genetics Glycogen Synthase Kinase 3 / metabolism* Imatinib Mesylate Immunoblotting Immunoprecipitation Janus Kinase 2 / genetics Janus Kinase 2 / metabolism* Mice Nocodazole / pharmacology Phosphatidylinositol 3-Kinases / genetics Phosphatidylinositol 3-Kinases / metabolism* Piperazines / pharmacology Proto-Oncogene Proteins c-akt / genetics Proto-Oncogene Proteins c-akt / metabolism* Pyrimidines / pharmacology fms-Like Tyrosine Kinase 3 / genetics fms-Like Tyrosine Kinase 3 / metabolism*
IF 2.776
Times Cited 22
WOS Category ONCOLOGY
Resource
Human and Animal Cells