Inhibiting BCKDK in triple negative breast cancer suppresses protein translation, impairs mitochondrial function, and potentiates doxorubicin cytotoxicity
Proposed mechanism. A Doxorubicin (DOX) targets the BCAA catabolic pathway in TNBCs, by downregulating BCKDK and augmenting clearance of intracellular BCKAs. B Genetic or pharmacological (high BT2 concentration) inhibition of BCKDK results in increased cell death, decreased intracellular BCKAs, dysr...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2021-09-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-021-00602-0 |
| _version_ | 1818663657370812416 |
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| author | Dipsikha Biswas Logan Slade Luke Duffley Neil Mueller Khoi Thien Dao Angella Mercer Shanmugasundaram Pakkiriswami Yassine El Hiani Petra C. Kienesberger Thomas Pulinilkunnil |
| author_facet | Dipsikha Biswas Logan Slade Luke Duffley Neil Mueller Khoi Thien Dao Angella Mercer Shanmugasundaram Pakkiriswami Yassine El Hiani Petra C. Kienesberger Thomas Pulinilkunnil |
| author_sort | Dipsikha Biswas |
| collection | DOAJ |
| description | Proposed mechanism. A Doxorubicin (DOX) targets the BCAA catabolic pathway in TNBCs, by downregulating BCKDK and augmenting clearance of intracellular BCKAs. B Genetic or pharmacological (high BT2 concentration) inhibition of BCKDK results in increased cell death, decreased intracellular BCKAs, dysregulated mitochondrial function, ATP insufficiency, SESN2 activation, and inhibition of mTORC1 signaling and protein synthesis. C BCKDK inhibition (siRNA mediated or low-BT2 concentration) exacerbates DOX-induced cytotoxicity and caspase activity. |
| first_indexed | 2024-12-17T05:20:20Z |
| format | Article |
| id | doaj.art-004b3d68105a445d9f322e3d584c6ae8 |
| institution | Directory Open Access Journal |
| issn | 2058-7716 |
| language | English |
| last_indexed | 2024-12-17T05:20:20Z |
| publishDate | 2021-09-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj.art-004b3d68105a445d9f322e3d584c6ae82022-12-21T22:01:59ZengNature Publishing GroupCell Death Discovery2058-77162021-09-017111210.1038/s41420-021-00602-0Inhibiting BCKDK in triple negative breast cancer suppresses protein translation, impairs mitochondrial function, and potentiates doxorubicin cytotoxicityDipsikha Biswas0Logan Slade1Luke Duffley2Neil Mueller3Khoi Thien Dao4Angella Mercer5Shanmugasundaram Pakkiriswami6Yassine El Hiani7Petra C. Kienesberger8Thomas Pulinilkunnil9Department of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie University, Dalhousie Medicine New BrunswickDepartment of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie University, Dalhousie Medicine New BrunswickDepartment of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie University, Dalhousie Medicine New BrunswickDepartment of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie University, Dalhousie Medicine New BrunswickDepartment of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie University, Dalhousie Medicine New BrunswickDepartment of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie University, Dalhousie Medicine New BrunswickDepartment of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie University, Dalhousie Medicine New BrunswickDepartment of Physiology and Biophysics, Faculty of Medicine, Dalhousie UniversityDepartment of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie University, Dalhousie Medicine New BrunswickDepartment of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie University, Dalhousie Medicine New BrunswickProposed mechanism. A Doxorubicin (DOX) targets the BCAA catabolic pathway in TNBCs, by downregulating BCKDK and augmenting clearance of intracellular BCKAs. B Genetic or pharmacological (high BT2 concentration) inhibition of BCKDK results in increased cell death, decreased intracellular BCKAs, dysregulated mitochondrial function, ATP insufficiency, SESN2 activation, and inhibition of mTORC1 signaling and protein synthesis. C BCKDK inhibition (siRNA mediated or low-BT2 concentration) exacerbates DOX-induced cytotoxicity and caspase activity.https://doi.org/10.1038/s41420-021-00602-0 |
| spellingShingle | Dipsikha Biswas Logan Slade Luke Duffley Neil Mueller Khoi Thien Dao Angella Mercer Shanmugasundaram Pakkiriswami Yassine El Hiani Petra C. Kienesberger Thomas Pulinilkunnil Inhibiting BCKDK in triple negative breast cancer suppresses protein translation, impairs mitochondrial function, and potentiates doxorubicin cytotoxicity Cell Death Discovery |
| title | Inhibiting BCKDK in triple negative breast cancer suppresses protein translation, impairs mitochondrial function, and potentiates doxorubicin cytotoxicity |
| title_full | Inhibiting BCKDK in triple negative breast cancer suppresses protein translation, impairs mitochondrial function, and potentiates doxorubicin cytotoxicity |
| title_fullStr | Inhibiting BCKDK in triple negative breast cancer suppresses protein translation, impairs mitochondrial function, and potentiates doxorubicin cytotoxicity |
| title_full_unstemmed | Inhibiting BCKDK in triple negative breast cancer suppresses protein translation, impairs mitochondrial function, and potentiates doxorubicin cytotoxicity |
| title_short | Inhibiting BCKDK in triple negative breast cancer suppresses protein translation, impairs mitochondrial function, and potentiates doxorubicin cytotoxicity |
| title_sort | inhibiting bckdk in triple negative breast cancer suppresses protein translation impairs mitochondrial function and potentiates doxorubicin cytotoxicity |
| url | https://doi.org/10.1038/s41420-021-00602-0 |
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