MCL-1 is a master regulator of cancer dependency on fatty acid oxidation
Summary: MCL-1 is an anti-apoptotic BCL-2 family protein essential for survival of diverse cell types and is a major driver of cancer and chemoresistance. The mechanistic basis for the oncogenic supremacy of MCL-1 among its anti-apoptotic homologs is unclear and implicates physiologic roles of MCL-1...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-10-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124722012864 |
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| author | Michelle S. Prew Utsarga Adhikary Dong Wook Choi Erika P. Portero Joao A. Paulo Pruthvi Gowda Amit Budhraja Joseph T. Opferman Steven P. Gygi Nika N. Danial Loren D. Walensky |
| author_facet | Michelle S. Prew Utsarga Adhikary Dong Wook Choi Erika P. Portero Joao A. Paulo Pruthvi Gowda Amit Budhraja Joseph T. Opferman Steven P. Gygi Nika N. Danial Loren D. Walensky |
| author_sort | Michelle S. Prew |
| collection | DOAJ |
| description | Summary: MCL-1 is an anti-apoptotic BCL-2 family protein essential for survival of diverse cell types and is a major driver of cancer and chemoresistance. The mechanistic basis for the oncogenic supremacy of MCL-1 among its anti-apoptotic homologs is unclear and implicates physiologic roles of MCL-1 beyond apoptotic suppression. Here we find that MCL-1-dependent hematologic cancer cells specifically rely on fatty acid oxidation (FAO) as a fuel source because of metabolic wiring enforced by MCL-1 itself. We demonstrate that FAO regulation by MCL-1 is independent of its anti-apoptotic activity, based on metabolomic, proteomic, and genomic profiling of MCL-1-dependent leukemia cells lacking an intact apoptotic pathway. Genetic deletion of Mcl-1 results in transcriptional downregulation of FAO pathway proteins such that glucose withdrawal triggers cell death despite apoptotic blockade. Our data reveal that MCL-1 is a master regulator of FAO, rendering MCL-1-driven cancer cells uniquely susceptible to treatment with FAO inhibitors. |
| first_indexed | 2024-04-12T10:10:23Z |
| format | Article |
| id | doaj.art-cc4932558c9943c9aa40dd9178059850 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-12T10:10:23Z |
| publishDate | 2022-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-cc4932558c9943c9aa40dd91780598502022-12-22T03:37:20ZengElsevierCell Reports2211-12472022-10-01411111445MCL-1 is a master regulator of cancer dependency on fatty acid oxidationMichelle S. Prew0Utsarga Adhikary1Dong Wook Choi2Erika P. Portero3Joao A. Paulo4Pruthvi Gowda5Amit Budhraja6Joseph T. Opferman7Steven P. Gygi8Nika N. Danial9Loren D. Walensky10Department of Pediatric Oncology and Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USADepartment of Pediatric Oncology and Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USADepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USADepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USADepartment of Cell Biology, Harvard Medical School, Boston, MA 02115, USADepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USADepartment of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USADepartment of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USADepartment of Cell Biology, Harvard Medical School, Boston, MA 02115, USADepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USADepartment of Pediatric Oncology and Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Corresponding authorSummary: MCL-1 is an anti-apoptotic BCL-2 family protein essential for survival of diverse cell types and is a major driver of cancer and chemoresistance. The mechanistic basis for the oncogenic supremacy of MCL-1 among its anti-apoptotic homologs is unclear and implicates physiologic roles of MCL-1 beyond apoptotic suppression. Here we find that MCL-1-dependent hematologic cancer cells specifically rely on fatty acid oxidation (FAO) as a fuel source because of metabolic wiring enforced by MCL-1 itself. We demonstrate that FAO regulation by MCL-1 is independent of its anti-apoptotic activity, based on metabolomic, proteomic, and genomic profiling of MCL-1-dependent leukemia cells lacking an intact apoptotic pathway. Genetic deletion of Mcl-1 results in transcriptional downregulation of FAO pathway proteins such that glucose withdrawal triggers cell death despite apoptotic blockade. Our data reveal that MCL-1 is a master regulator of FAO, rendering MCL-1-driven cancer cells uniquely susceptible to treatment with FAO inhibitors.http://www.sciencedirect.com/science/article/pii/S2211124722012864CP: CancerCP: Metabolism |
| spellingShingle | Michelle S. Prew Utsarga Adhikary Dong Wook Choi Erika P. Portero Joao A. Paulo Pruthvi Gowda Amit Budhraja Joseph T. Opferman Steven P. Gygi Nika N. Danial Loren D. Walensky MCL-1 is a master regulator of cancer dependency on fatty acid oxidation Cell Reports CP: Cancer CP: Metabolism |
| title | MCL-1 is a master regulator of cancer dependency on fatty acid oxidation |
| title_full | MCL-1 is a master regulator of cancer dependency on fatty acid oxidation |
| title_fullStr | MCL-1 is a master regulator of cancer dependency on fatty acid oxidation |
| title_full_unstemmed | MCL-1 is a master regulator of cancer dependency on fatty acid oxidation |
| title_short | MCL-1 is a master regulator of cancer dependency on fatty acid oxidation |
| title_sort | mcl 1 is a master regulator of cancer dependency on fatty acid oxidation |
| topic | CP: Cancer CP: Metabolism |
| url | http://www.sciencedirect.com/science/article/pii/S2211124722012864 |
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