Journal Article

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

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

2025

Overview

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) CoMMpassSM 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. Triacsin C inhibition of the acyl‐CoA synthetase long chain (ACSL) family decreases multiple myeloma cell survival, proliferation, mitochondrial respiration, and membrane potential. Made with Biorender.com.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: ACSL / Antibiotics / Apoptosis / Apoptosis - drug effects / Blood Cancer; Acute Myeloid Leukemia / Bone marrow / Cancer therapies / Cell growth / Cell Line, Tumor / cell metabolism / Cell proliferation / Cell Proliferation - drug effects / Cell Survival - drug effects / Cell viability / Coenzyme A / Coenzyme A Ligases - antagonists & inhibitors / Coenzyme A Ligases - genetics / Coenzyme A Ligases - metabolism / Colorectal cancer / Electron transport / Endoplasmic reticulum / Enzyme Inhibitors - pharmacology / Esters / fatty acid / Fatty acids / Ferroptosis / Gene expression / Genomics / Glioma / hematological malignancies / Humans / Isoenzymes / Leukemia / Long-Chain-Fatty-Acid-CoA Ligase / Membrane potential / Metabolism / Metabolites / Mitochondria / Mitochondria - drug effects / Mitochondria - metabolism / Mitochondria - pathology / Multiple myeloma / Multiple Myeloma - drug therapy / Multiple Myeloma - enzymology / Multiple Myeloma - genetics / Multiple Myeloma - metabolism / Multiple Myeloma - pathology / Oxidative phosphorylation / Phosphorylation / Plasma cells / Proteomics / Sequence analysis / Survival analysis / Therapeutic targets / Triacsin C / Triazenes / Tumor cell lines