BIRC6 mediates imatinib resistance independently of Mcl-1
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Okumu, Denis O, et al. Birc6 Mediates Imatinib Resistance Independently of Mcl-1. 2017. https://doi.org/10.17615/qjbq-b671APA
Okumu, D., East, M., Levine, M., Herring, L., Zhang, R., Gilbert, T., Litchfield, D., Zhang, Y., & Graves, L. (2017). BIRC6 mediates imatinib resistance independently of Mcl-1. https://doi.org/10.17615/qjbq-b671Chicago
Okumu, Denis O., Michael P East, Merlin Levine, Laura E Herring, Raymond Zhang, Thomas S. K Gilbert, David W Litchfield et al. 2017. Birc6 Mediates Imatinib Resistance Independently of Mcl-1. https://doi.org/10.17615/qjbq-b671- Creator
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Okumu, Denis O.
- Affiliation: School of Medicine, Department of Pharmacology
- Other Affiliation: University of North Carolina at Chapel Hill
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East, Michael P.
- Affiliation: School of Medicine, Department of Pharmacology
- Other Affiliation: University of North Carolina at Chapel Hill
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Levine, Merlin
- Affiliation: College of Arts and Sciences, Department of Chemistry
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Herring, Laura E.
- Affiliation: School of Medicine, Department of Pharmacology
- Other Affiliation: University of North Carolina at Chapel Hill
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Zhang, Raymond
- Affiliation: School of Medicine, Department of Pharmacology
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Gilbert, Thomas S. K.
- Affiliation: School of Medicine, Department of Pharmacology
- Other Affiliation: University of North Carolina at Chapel Hill
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Litchfield, David W.
- Other Affiliation: Department of Biochemistry; Schulich School of Medicine and Dentistry; Western University
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Zhang, Yanping
- Affiliation: School of Medicine, Department of Pharmacology
- Other Affiliation: Department of Radiation Oncology
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Graves, Lee M.
- Affiliation: School of Medicine, Department of Pharmacology
- Other Affiliation: University of North Carolina at Chapel Hill
- 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 active in MYL-R cells, we tested the effects of Lyn inhibition on BIRC6 and Mcl-1. RNAi-mediated knockdown or inhibition of Lyn (dasatinib/ponatinib) reduced BIRC6 protein stability and increased caspase activation. Inhibition of Lyn also increased formation of an N-terminal BIRC6 fragment in parallel with reduced amount of the BIRC6 phosphopeptide, suggesting that Lyn may regulate BIRC6 phosphorylation and stability. In summary, our data show that BIRC6 stability is dependent on Lyn, and that BIRC6 mediates imatinib sensitivity independently of Mcl-1 or CDK9. Hence, BIRC6 may be a novel target for the treatment of drug-resistant CML where Mcl-1 or CDK9 inhibitors have failed.
- Date of publication
- 2017
- Keyword
- DOI
- Identifier
- PMCID: PMC5433768
- Publisher DOI: https://doi.org/10.1371/journal.pone.0177871
- Onescience id: 968099adf57541bed16f1d73508b6e555ecdd608
- PMID: 28520795
- Resource type
- Article
- Rights statement
- In Copyright
- Journal title
- PloS One
- Journal volume
- 12
- Journal issue
- 5
- Page start
- e0177871
- Language
- English
- ISSN
- 1932-6203
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