AKT inhibition sensitizes acute leukemia cells to S63845-induced apoptosis
ABSTRACTThe MCL1 inhibitors are undergoing clinical testing for multiple leukemia. However, because that MCL1 inhibition has on-target hematopoietic, hepatic and cardiac toxicities, there is substantial interest in finding agents can sensitize leukemia cells to the MCL1 inhibitors. Here we describe...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2023-12-01
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| Series: | Hematology |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/16078454.2023.2214465 |
| _version_ | 1797821336368709632 |
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| author | Yunjian Li Liang Du Kaiqin Ye Xiao Sun Lei Hu Shan Gao Haiming Dai |
| author_facet | Yunjian Li Liang Du Kaiqin Ye Xiao Sun Lei Hu Shan Gao Haiming Dai |
| author_sort | Yunjian Li |
| collection | DOAJ |
| description | ABSTRACTThe MCL1 inhibitors are undergoing clinical testing for multiple leukemia. However, because that MCL1 inhibition has on-target hematopoietic, hepatic and cardiac toxicities, there is substantial interest in finding agents can sensitize leukemia cells to the MCL1 inhibitors. Here we describe that the AKT inhibitors MK-2206 and Gsk690693 sensitize multiple leukemia cells to the MCL1 inhibitor S63845. Further experiments demonstrate that MK-2206 and Gsk690693 sensitize S63845 through the mitochondrial apoptosis pathway. Moreover, MK-2206 downregulates the anti-apoptotic protein BCLXL and induces the BH3-only pro-apoptotic protein BAD dephosphorylation and mitochondrial translocation. Knockdown of BAD significantly inhibits MK-2206-induced sensitization to S63845. Thus, our results suggest that MK-2206 sensitizes multiple leukemia cells to S63845-induced apoptosis, with the mechanisms involving BAD dephosphorylation and BCLXL downregulation. |
| first_indexed | 2024-03-13T09:51:14Z |
| format | Article |
| id | doaj.art-14b7d55fc8e442c78e82960dd07a1c28 |
| institution | Directory Open Access Journal |
| issn | 1607-8454 |
| language | English |
| last_indexed | 2024-03-13T09:51:14Z |
| publishDate | 2023-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Hematology |
| spelling | doaj.art-14b7d55fc8e442c78e82960dd07a1c282023-05-24T08:44:29ZengTaylor & Francis GroupHematology1607-84542023-12-0128110.1080/16078454.2023.2214465AKT inhibition sensitizes acute leukemia cells to S63845-induced apoptosisYunjian Li0Liang Du1Kaiqin Ye2Xiao Sun3Lei Hu4Shan Gao5Haiming Dai6Basic Medicine College, Anhui Medical University, Hefei, People’s Republic of ChinaBasic Medicine College, Anhui Medical University, Hefei, People’s Republic of ChinaAnhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, People’s Republic of ChinaAnhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, People’s Republic of ChinaAnhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, People’s Republic of ChinaBasic Medicine College, Anhui Medical University, Hefei, People’s Republic of ChinaBasic Medicine College, Anhui Medical University, Hefei, People’s Republic of ChinaABSTRACTThe MCL1 inhibitors are undergoing clinical testing for multiple leukemia. However, because that MCL1 inhibition has on-target hematopoietic, hepatic and cardiac toxicities, there is substantial interest in finding agents can sensitize leukemia cells to the MCL1 inhibitors. Here we describe that the AKT inhibitors MK-2206 and Gsk690693 sensitize multiple leukemia cells to the MCL1 inhibitor S63845. Further experiments demonstrate that MK-2206 and Gsk690693 sensitize S63845 through the mitochondrial apoptosis pathway. Moreover, MK-2206 downregulates the anti-apoptotic protein BCLXL and induces the BH3-only pro-apoptotic protein BAD dephosphorylation and mitochondrial translocation. Knockdown of BAD significantly inhibits MK-2206-induced sensitization to S63845. Thus, our results suggest that MK-2206 sensitizes multiple leukemia cells to S63845-induced apoptosis, with the mechanisms involving BAD dephosphorylation and BCLXL downregulation.https://www.tandfonline.com/doi/10.1080/16078454.2023.2214465S63845BCL2 familyAKTMK-2206BAD |
| spellingShingle | Yunjian Li Liang Du Kaiqin Ye Xiao Sun Lei Hu Shan Gao Haiming Dai AKT inhibition sensitizes acute leukemia cells to S63845-induced apoptosis Hematology S63845 BCL2 family AKT MK-2206 BAD |
| title | AKT inhibition sensitizes acute leukemia cells to S63845-induced apoptosis |
| title_full | AKT inhibition sensitizes acute leukemia cells to S63845-induced apoptosis |
| title_fullStr | AKT inhibition sensitizes acute leukemia cells to S63845-induced apoptosis |
| title_full_unstemmed | AKT inhibition sensitizes acute leukemia cells to S63845-induced apoptosis |
| title_short | AKT inhibition sensitizes acute leukemia cells to S63845-induced apoptosis |
| title_sort | akt inhibition sensitizes acute leukemia cells to s63845 induced apoptosis |
| topic | S63845 BCL2 family AKT MK-2206 BAD |
| url | https://www.tandfonline.com/doi/10.1080/16078454.2023.2214465 |
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