Inhibition of acyl-CoA synthetase long-chain isozymes decreases multiple myeloma cell proliferation and causes mitochondrial dysfunction

Connor S Murphy; Heather Fairfield; Victoria E DeMambro; Samaa Fadel; Carlos A Gartner; Michelle Karam; Christian Potts; Princess Rodriguez; Ya-Wei Qiang; Habib Hamidi; Xiangnan Guan; Calvin P H Vary; Michaela R Reagan

doi:10.1002/1878-0261.13794

Inhibition of acyl-CoA synthetase long-chain isozymes decreases multiple myeloma cell proliferation and causes mitochondrial dysfunction

Mol Oncol. 2025 Jan 23. doi: 10.1002/1878-0261.13794. Online ahead of print.

Authors

Connor S Murphy^{1

2}, Heather Fairfield^{1

3}, Victoria E DeMambro^{1

2}, Samaa Fadel^{1

3

4}, Carlos A Gartner^{1

2}, Michelle Karam¹, Christian Potts¹, Princess Rodriguez⁵, Ya-Wei Qiang¹, Habib Hamidi⁶, Xiangnan Guan⁶, Calvin P H Vary^{1

2

3}, Michaela R Reagan^{1

2

3}

Affiliations

¹ Center for Molecular Medicine, MaineHealth Institute for Research, Scarborough, ME, USA.
² University of Maine Graduate School of Biomedical Science and Engineering, University of Maine, Orono, ME, USA.
³ School of Medicine, Tufts University, Boston, MA, USA.
⁴ University of New England, Biddeford, ME, USA.
⁵ Vermont Integrative Genomics Resource DNA Facility, University of Vermont, Burlington, VT, USA.
⁶ Genentech, Inc., San Francisco, CA, USA.

PMID: 39853696
DOI: 10.1002/1878-0261.13794

Abstract

Multiple myeloma (MM) is an incurable cancer of plasma cells with a 5-year survival rate of 59%. Dysregulation of fatty acid (FA) metabolism is associated with MM development and progression; however, the underlying mechanisms remain unclear. Herein, we explore the roles of long-chain fatty acid coenzyme A ligase (ACSL) family members in MM. ACSLs convert free long-chain fatty acids into fatty acyl-CoA esters and play key roles in catabolic and anabolic fatty acid metabolism. Analysis of the Multiple Myeloma Research Foundation (MMRF) CoMMpass^SM study showed that high ACSL1 and ACSL4 expression in myeloma cells are both associated with worse clinical outcomes for MM patients. Cancer Dependency Map (DepMap) data showed that all five ACSLs have negative Chronos scores, and ACSL3 and ACSL4 were among the top 25% Hallmark Fatty Acid Metabolism genes that support myeloma cell line fitness. Inhibition of ACSLs in myeloma cell lines in vitro, using the pharmacological inhibitor Triacsin C (TriC), increased apoptosis, decreased proliferation, and decreased cell viability, in a dose- and time-dependent manner. RNA-sequencing analysis of MM.1S cells treated with TriC showed a significant enrichment in apoptosis, ferroptosis, and endoplasmic reticulum (ER) stress, and proteomic analysis of these cells revealed enriched pathways for mitochondrial dysfunction and oxidative phosphorylation. TriC also rewired mitochondrial metabolism by decreasing mitochondrial membrane potential, increasing mitochondrial superoxide levels, decreasing mitochondrial ATP production rates, and impairing cellular respiration. Overall, our data support the hypothesis that suppression of ACSLs in myeloma cells is a novel metabolic target in MM that inhibits their viability, implicating this family as a promising therapeutic target in treating myeloma.

Keywords: ACSL; Triacsin C; cell metabolism; fatty acid; hematological malignancies; multiple myeloma.

Abstract

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