Targeting the fatty acid binding proteins disrupts multiple myeloma cell cycle progression and MYC signaling
- Maine Health Institute for Research, United States
- Maine Medical Center Research Institute, United States
- Dana-Farber Cancer Institute, United States
- University of Vermont, United States
- University of New England, United States
Abstract
Multiple myeloma is an incurable plasma cell malignancy with only a 53% 5-year survival rate. There is a critical need to find new multiple myeloma vulnerabilities and therapeutic avenues. Herein, we identified and explored a novel multiple myeloma target: the fatty acid binding protein (FABP) family. In our work, myeloma cells were treated with FABP inhibitors (BMS3094013 and SBFI-26) and examined in vivo and in vitro for cell cycle state, proliferation, apoptosis, mitochondrial membrane potential, cellular metabolism (oxygen consumption rates and fatty acid oxidation), and DNA methylation properties. Myeloma cell responses to BMS309403, SBFI-26, or both, were also assessed with RNA sequencing (RNA-Seq) and proteomic analysis, and confirmed with western blotting and qRT-PCR. Myeloma cell dependency on FABPs was assessed using the Cancer Dependency Map (DepMap). Finally, MM patient datasets (CoMMpass and GEO) were mined for FABP expression correlations with clinical outcomes. We found that myeloma cells treated with FABPi or with FABP5 knockout (generated via CRISPR/Cas9 editing) exhibited diminished proliferation, increased apoptosis, and metabolic changes in vitro. FABPi had mixed results in vivo, in two pre-clinical MM mouse models, suggesting optimization of in vivo delivery, dosing, or type of FABP inhibitors will be needed before clinical applicability. FABPi negatively impacted mitochondrial respiration and reduced expression of MYC and other key signaling pathways in MM cells in vitro. Clinical data demonstrated worse overall and progression-free survival in patients with high FABP5 expression in tumor cells. Overall, this study establishes the FABP family as a potentially new target in multiple myeloma. In MM cells, FABPs have a multitude of actions and cellular roles that result in the support of myeloma progression. Further research into the FABP family in MM is warrented, especially into the effective translation of targeting these in vivo.
Data availability
The clinical datasets used and analyzed during the current study are from Oncomine or data related to accession number GEO:GSE6477. RNA-seq data have been deposited in the NCBI Gene Expression Omnibus (GEO) database with the accession number GSE190699. The mass spectrometry proteomic data have been deposited to the ProteomeXchange Consortium via the PRIDE partner respository with the dataset identifier PXD032829.
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The Fatty Acid Binding Protein Family Represents a Novel Target in Multiple MyelomaNCBI Gene Expression Omnibus, GSE190699.
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The Fatty Acid Binding Protein Family Represents a Novel Target in Multiple MyelomaProteomeXchange Consortium, PXD032829.
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Expression data from different stages of plasma cell neoplasmNCBI Gene Expression Omnibus, GSE6477.
Article and author information
Author details
Funding
National Cancer Institute (F31CA257695)
- Connor S Murphy
National Cancer Institute (R37CA245330)
- Michaela R Reagan
National Cancer Institute (R50CA265331)
- Heather Fairfield
National Institute of General Medical Sciences (P20GM103449)
- Julie A Dragon
National Institute of General Medical Sciences (U54GM115516)
- Michaela R Reagan
National Institute of General Medical Sciences (P20GM121301)
- Calvin Vary
National Institute of General Medical Sciences (P20GM121301)
- Michaela R Reagan
American Cancer Society (RSG-19-037-01-LIB)
- Michaela R Reagan
American Cancer Society (IRG-16-191-33)
- Michaela R Reagan
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All experimental studies and procedures involving mice were performed in accordance with approved protocols from the Maine Medical Center Research Institute's (Scarborough, Maine, USA) Institutional Animal Care and Use Committee (protocols #2111 or #1812).
Human subjects: Primary human MSCs were isolated from deidentified cancellous bone from the acetabulum received from donors (men and women) after total hip arthroplasty through the MaineHealth Biobank after IRB approval and informed consent (Biobank IRB # 2526).
Copyright
© 2023, Farrell et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Targeting the fatty acid binding proteins disrupts multiple myeloma cell cycle progression and MYC signaling
eLife 12:e81184.
https://doi.org/10.7554/eLife.81184
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