MCL-1 is a master regulator of cancer dependency on fatty acid oxidation.

Abstract

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.

• Authors: 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
• Journal: Cell reports (Cell Rep) Vol. 41 Issue 1 Pg. 111445 (10 04 2022) ISSN: 2211-1247 [Electronic] United States
• PMID: 36198266 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Apoptosis Regulatory Proteins
• Fatty Acids
• Myeloid Cell Leukemia Sequence 1 Protein
• Proto-Oncogene Proteins c-bcl-2
• Glucose

Topics

• Apoptosis
• Apoptosis Regulatory Proteins (metabolism)
• Cell Line, Tumor
• Fatty Acids
• Glucose
• Myeloid Cell Leukemia Sequence 1 Protein (genetics, metabolism)
• Neoplasms (genetics)
• Proteomics
• Proto-Oncogene Proteins c-bcl-2 (metabolism)