Bay 61-3606 sensitizes TRAIL-induced Apoptosis by downregulating Mcl-1 in breast cancer cells

So Young Kim; Sang Eun Park; Sang Mi Shim; Sojung Park; Kyung Kon Kim; Seong Yun Jeong; Eun Kyung Choi; Jung Jin Hwang; Dong Hoon Jin; Christopher Doosoon Chung; Inki Kim

doi:10.1371/journal.pone.0146073

Bay 61-3606 sensitizes TRAIL-induced Apoptosis by downregulating Mcl-1 in breast cancer cells

So Young Kim, Sang Eun Park, Sang Mi Shim, Sojung Park, Kyung Kon Kim, Seong Yun Jeong, Eun Kyung Choi, Jung Jin Hwang, Dong Hoon Jin, Christopher Doosoon Chung, Inki Kim

Department of Internal Medicine

Research output: Contribution to journal › Article › peer-review

15 Scopus citations

Abstract

Breast cancer cells generally develop resistance to TNF-Related Apoptosis-Inducing Ligand (TRAIL) and, therefore, assistance from sensitizers is required. In our study, we have demonstrated that Spleen tyrosine kinase (Syk) inhibitor Bay 61-3606 was identified as a TRAIL sensitizer. Amplification of TRAIL-induced apoptosis by Bay 61-3606 was accompanied by the strong activation of Bak, caspases, and DNA fragmentation. In mechanism of action, Bay 61-3606 sensitized cells to TRAIL via two mechanisms regulating myeloid cell leukemia sequence-1 (Mcl-1). First, Bay 61-3606 triggered ubiquitin-dependent degradation of Mcl-1 by regulating Mcl-1 phosphorylation. Second, Bay 61-3606 downregulates Mcl-1 expression at the transcription level. In this context, Bay 61-3606 acted as an inhibitor of Cyclin-Dependent Kinase (CDK) 9 rather than Syk. In summary, Bay 61-3606 downregulates Mcl-1 expression in breast cancer cells and sensitizes cancer cells to TRAIL-mediated apoptosis.

Original language	English
Article number	e0146073
Journal	PLoS ONE
Volume	10
Issue number	12
DOIs	https://doi.org/10.1371/journal.pone.0146073
State	Published - 1 Dec 2015

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Publisher Copyright:
© 2015 Kim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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title = "Bay 61-3606 sensitizes TRAIL-induced Apoptosis by downregulating Mcl-1 in breast cancer cells",

abstract = "Breast cancer cells generally develop resistance to TNF-Related Apoptosis-Inducing Ligand (TRAIL) and, therefore, assistance from sensitizers is required. In our study, we have demonstrated that Spleen tyrosine kinase (Syk) inhibitor Bay 61-3606 was identified as a TRAIL sensitizer. Amplification of TRAIL-induced apoptosis by Bay 61-3606 was accompanied by the strong activation of Bak, caspases, and DNA fragmentation. In mechanism of action, Bay 61-3606 sensitized cells to TRAIL via two mechanisms regulating myeloid cell leukemia sequence-1 (Mcl-1). First, Bay 61-3606 triggered ubiquitin-dependent degradation of Mcl-1 by regulating Mcl-1 phosphorylation. Second, Bay 61-3606 downregulates Mcl-1 expression at the transcription level. In this context, Bay 61-3606 acted as an inhibitor of Cyclin-Dependent Kinase (CDK) 9 rather than Syk. In summary, Bay 61-3606 downregulates Mcl-1 expression in breast cancer cells and sensitizes cancer cells to TRAIL-mediated apoptosis.",

author = "Kim, {So Young} and Park, {Sang Eun} and Shim, {Sang Mi} and Sojung Park and Kim, {Kyung Kon} and Jeong, {Seong Yun} and Choi, {Eun Kyung} and Hwang, {Jung Jin} and Jin, {Dong Hoon} and Chung, {Christopher Doosoon} and Inki Kim",

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AU - Kim, So Young

AU - Park, Sang Eun

AU - Shim, Sang Mi

AU - Park, Sojung

AU - Kim, Kyung Kon

AU - Jeong, Seong Yun

AU - Choi, Eun Kyung

AU - Hwang, Jung Jin

AU - Jin, Dong Hoon

AU - Chung, Christopher Doosoon

AU - Kim, Inki

N1 - Publisher Copyright: © 2015 Kim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PY - 2015/12/1

Y1 - 2015/12/1

N2 - Breast cancer cells generally develop resistance to TNF-Related Apoptosis-Inducing Ligand (TRAIL) and, therefore, assistance from sensitizers is required. In our study, we have demonstrated that Spleen tyrosine kinase (Syk) inhibitor Bay 61-3606 was identified as a TRAIL sensitizer. Amplification of TRAIL-induced apoptosis by Bay 61-3606 was accompanied by the strong activation of Bak, caspases, and DNA fragmentation. In mechanism of action, Bay 61-3606 sensitized cells to TRAIL via two mechanisms regulating myeloid cell leukemia sequence-1 (Mcl-1). First, Bay 61-3606 triggered ubiquitin-dependent degradation of Mcl-1 by regulating Mcl-1 phosphorylation. Second, Bay 61-3606 downregulates Mcl-1 expression at the transcription level. In this context, Bay 61-3606 acted as an inhibitor of Cyclin-Dependent Kinase (CDK) 9 rather than Syk. In summary, Bay 61-3606 downregulates Mcl-1 expression in breast cancer cells and sensitizes cancer cells to TRAIL-mediated apoptosis.

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Bay 61-3606 sensitizes TRAIL-induced Apoptosis by downregulating Mcl-1 in breast cancer cells

Abstract

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