title: Selective leukemia cell death by activation of the double-stranded RNA-dependent protein kinase PKR.
abstract: Deregulated activity of the BCR-ABL tyrosine kinase encoded by the Bcr-Abl oncogene represents an important therapeutic target for all the chronic myelogenous leukemia (CML) phases. In this study, we sought to identify targeted PKR activation by Bcr-Abl AS RNA, an anti-sense RNA complementary to the unique mRNA fragments flanking the fusion point of Bcr-Abl, which can be used as an effective anti-leukemia strategy in K562 cells. Moreover, we observed expression of Bcr-Abl AS RNA in K562 cells which resulted in selective apoptosis induction through specific activation of PKR, leading to phosphorylation of eIF2α, global inhibition of protein synthesis, caspase-8 activation and BAX up-regulation. The targeted PKR activation and induced apoptosis were reversed by the PKR inhibitor 2-aminopurine. Taken together, our results indicate that targeted PKR activation led to selective apoptosis induction in K562 cells, which correlated with caspase-8 activity and enhanced expression of BAX.
authors.affiliation: Department of Clinical Hematology, Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Chongqing Medical University, Chongqing 400016, P.R. China.
authors.forename: Ya-Juan
authors.initials: YJ
authors.lastname: Li
authors.forename: Jian-Ming
authors.initials: JM
authors.lastname: Zeng
authors.forename: Shi-Feng
authors.initials: SF
authors.lastname: Huang
authors.forename: Xiao-Zhong
authors.initials: XZ
authors.lastname: Wang
authors.forename: Shi-Qiao
authors.initials: SQ
authors.lastname: Zhao
authors.forename: Wei-Jun
authors.initials: WJ
authors.lastname: Bai
authors.forename: Wei-Xi
authors.initials: WX
authors.lastname: Cao
authors.forename: Zong-Gan
authors.initials: ZG
authors.lastname: Huang
authors.forename: Wen-Li
authors.initials: WL
authors.lastname: Feng
mesh_terms: D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle; D016923:Cell Death; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000502:physiology; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D020868:Gene Silencing; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology* / Q000473:pathology; D008954:Models, Biological; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016372:RNA, Antisense / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism*
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D016372:RNA, Antisense; D051028:bcl-2-Associated X Protein; D016044:Fusion Proteins, bcr-abl; D019892:eIF-2 Kinase; D020169:Caspases