Eltrombopag directly activates BAK and induces apoptosis
Abstract Small molecule direct BAK activators can potentially be used for the development of anti-cancer drugs or as tools to study BAK activation. The thrombopoietin receptor agonist eltrombopag (Eltro) inhibits BAX activation and BAX-mediated apoptosis. Here we report that, in contrast to its func...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-07-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-05918-6 |
| _version_ | 1797789509999394816 |
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| author | Meng Chen Lei Hu Xuyuan Bao Kaiqin Ye Yunjian Li Zhiyong Zhang Scott H. Kaufmann Jun Xiao Haiming Dai |
| author_facet | Meng Chen Lei Hu Xuyuan Bao Kaiqin Ye Yunjian Li Zhiyong Zhang Scott H. Kaufmann Jun Xiao Haiming Dai |
| author_sort | Meng Chen |
| collection | DOAJ |
| description | Abstract Small molecule direct BAK activators can potentially be used for the development of anti-cancer drugs or as tools to study BAK activation. The thrombopoietin receptor agonist eltrombopag (Eltro) inhibits BAX activation and BAX-mediated apoptosis. Here we report that, in contrast to its function as a BAX inhibitor, Eltro directly binds BAK but induces its activation in vitro. Moreover, Eltro induces or sensitizes BAK-dependent cell death in mouse embryonic fibroblasts (MEFs) and Jurkat cells. Chemical shift perturbation analysis by NMR indicates that Eltro binds to the BAK α4/α6/α7 groove to initiate BAK activation. Further molecular docking by HADDOCK suggests that several BAK residues, including R156, F157, and H164, play an important role in the interaction with Eltro. The introduction of an R156E mutation in the BAK α4/α6/α7 groove not only decreases Eltro binding and Eltro-induced BAK activation in vitro but also diminishes Eltro-induced apoptosis. Thus, our data suggest that Eltro directly induces BAK activation and BAK-dependent apoptosis, providing a starting point for the future development of more potent and selective direct BAK activators. |
| first_indexed | 2024-03-13T01:51:45Z |
| format | Article |
| id | doaj.art-9794af5093d74fa5bbf1e8012c757380 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-13T01:51:45Z |
| publishDate | 2023-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-9794af5093d74fa5bbf1e8012c7573802023-07-02T11:28:13ZengNature Publishing GroupCell Death and Disease2041-48892023-07-0114711010.1038/s41419-023-05918-6Eltrombopag directly activates BAK and induces apoptosisMeng Chen0Lei Hu1Xuyuan Bao2Kaiqin Ye3Yunjian Li4Zhiyong Zhang5Scott H. Kaufmann6Jun Xiao7Haiming Dai8Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of SciencesSchool of Preclinical Medicine, Wannan Medical CollegeDepartment of Physics, University of Science and Technology of ChinaAnhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of SciencesAnhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of SciencesDepartment of Physics, University of Science and Technology of ChinaDivision of Oncology Research, Mayo ClinicDepartment of Urology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of ChinaAnhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of SciencesAbstract Small molecule direct BAK activators can potentially be used for the development of anti-cancer drugs or as tools to study BAK activation. The thrombopoietin receptor agonist eltrombopag (Eltro) inhibits BAX activation and BAX-mediated apoptosis. Here we report that, in contrast to its function as a BAX inhibitor, Eltro directly binds BAK but induces its activation in vitro. Moreover, Eltro induces or sensitizes BAK-dependent cell death in mouse embryonic fibroblasts (MEFs) and Jurkat cells. Chemical shift perturbation analysis by NMR indicates that Eltro binds to the BAK α4/α6/α7 groove to initiate BAK activation. Further molecular docking by HADDOCK suggests that several BAK residues, including R156, F157, and H164, play an important role in the interaction with Eltro. The introduction of an R156E mutation in the BAK α4/α6/α7 groove not only decreases Eltro binding and Eltro-induced BAK activation in vitro but also diminishes Eltro-induced apoptosis. Thus, our data suggest that Eltro directly induces BAK activation and BAK-dependent apoptosis, providing a starting point for the future development of more potent and selective direct BAK activators.https://doi.org/10.1038/s41419-023-05918-6 |
| spellingShingle | Meng Chen Lei Hu Xuyuan Bao Kaiqin Ye Yunjian Li Zhiyong Zhang Scott H. Kaufmann Jun Xiao Haiming Dai Eltrombopag directly activates BAK and induces apoptosis Cell Death and Disease |
| title | Eltrombopag directly activates BAK and induces apoptosis |
| title_full | Eltrombopag directly activates BAK and induces apoptosis |
| title_fullStr | Eltrombopag directly activates BAK and induces apoptosis |
| title_full_unstemmed | Eltrombopag directly activates BAK and induces apoptosis |
| title_short | Eltrombopag directly activates BAK and induces apoptosis |
| title_sort | eltrombopag directly activates bak and induces apoptosis |
| url | https://doi.org/10.1038/s41419-023-05918-6 |
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