BIRC6 mediates imatinib resistance independently of Mcl-1

PloS One
Denis O OkumuLee M Graves

Abstract

Baculoviral IAP repeat containing 6 (BIRC6) is a member of the inhibitors of apoptosis proteins (IAPs), a family of functionally and structurally related proteins that inhibit apoptosis. BIRC6 has been implicated in drug resistance in several different human cancers, however mechanisms regulating BIRC6 have not been extensively explored. Our phosphoproteomic analysis of an imatinib-resistant chronic myelogenous leukemia (CML) cell line (MYL-R) identified increased amounts of a BIRC6 peptide phosphorylated at S480, S482, and S486 compared to imatinib-sensitive CML cells (MYL). Thus we investigated the role of BIRC6 in mediating imatinib resistance and compared it to the well-characterized anti-apoptotic protein, Mcl-1. Both BIRC6 and Mcl-1 were elevated in MYL-R compared to MYL cells. Lentiviral shRNA knockdown of BIRC6 in MYL-R cells increased imatinib-stimulated caspase activation and resulted in a ~20-25-fold increase in imatinib sensitivity, without affecting Mcl-1. Treating MYL-R cells with CDK9 inhibitors decreased BIRC6 mRNA, but not BIRC6 protein levels. By contrast, while CDK9 inhibitors reduced Mcl-1 mRNA and protein, they did not affect imatinib sensitivity. Since the Src family kinase Lyn is highly expressed and acti...Continue Reading

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Citations

Oct 27, 2017·Apoptosis : an International Journal on Programmed Cell Death·Mervat S MohamedAyat G Ali
Oct 1, 2020·The Analyst·Mustafa Gani SürmenNesrin Emekli
Dec 28, 2019·Biochimica Et Biophysica Acta. General Subjects·Denis O OkumuLee M Graves

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Methods Mentioned

BETA
electrophoresis
PCR
Assay
flow cytometry
immunoprecipitation

Software Mentioned

MitoCasp
QExactive
GraphPad Prism SoftWare
GraphPad Prism
Andromeda
Excel
Perseus
MAXQUANT

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