Inhibition of acyl‐CoA synthetase long‐chain isozymes decreases multiple myeloma cell proliferation and causes mitochondrial dysfunction
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 coe...
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| Format: | Article |
| Language: | English |
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Wiley
2025-06-01
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| Series: | Molecular Oncology |
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| Online Access: | https://doi.org/10.1002/1878-0261.13794 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Connor S. Murphy |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-7ab95cf55cb04947a91cd7be80705b08 |
| institution | Kabale University |
| issn | 1574-7891 1878-0261 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj-art-7ab95cf55cb04947a91cd7be80705b082025-08-20T03:44:52ZengWileyMolecular Oncology1574-78911878-02612025-06-011961687170610.1002/1878-0261.13794Inhibition of acyl‐CoA synthetase long‐chain isozymes decreases multiple myeloma cell proliferation and causes mitochondrial dysfunctionConnor S. Murphy0Heather Fairfield1Victoria E. DeMambro2Samaa Fadel3Carlos A. Gartner4Michelle Karam5Christian Potts6Princess Rodriguez7Ya‐Wei Qiang8Habib Hamidi9Xiangnan Guan10Calvin P. H. Vary11Michaela R. Reagan12Center for Molecular Medicine MaineHealth Institute for Research Scarborough ME USACenter for Molecular Medicine MaineHealth Institute for Research Scarborough ME USACenter for Molecular Medicine MaineHealth Institute for Research Scarborough ME USACenter for Molecular Medicine MaineHealth Institute for Research Scarborough ME USACenter for Molecular Medicine MaineHealth Institute for Research Scarborough ME USACenter for Molecular Medicine MaineHealth Institute for Research Scarborough ME USACenter for Molecular Medicine MaineHealth Institute for Research Scarborough ME USAVermont Integrative Genomics Resource DNA Facility University of Vermont Burlington VT USACenter for Molecular Medicine MaineHealth Institute for Research Scarborough ME USAGenentech, Inc. San Francisco CA USAGenentech, Inc. San Francisco CA USACenter for Molecular Medicine MaineHealth Institute for Research Scarborough ME USACenter for Molecular Medicine MaineHealth Institute for Research Scarborough ME USAMultiple 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.https://doi.org/10.1002/1878-0261.13794ACSLcell metabolismfatty acidhematological malignanciesmultiple myelomaTriacsin C |
| spellingShingle | 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 Inhibition of acyl‐CoA synthetase long‐chain isozymes decreases multiple myeloma cell proliferation and causes mitochondrial dysfunction Molecular Oncology ACSL cell metabolism fatty acid hematological malignancies multiple myeloma Triacsin C |
| title | Inhibition of acyl‐CoA synthetase long‐chain isozymes decreases multiple myeloma cell proliferation and causes mitochondrial dysfunction |
| title_full | Inhibition of acyl‐CoA synthetase long‐chain isozymes decreases multiple myeloma cell proliferation and causes mitochondrial dysfunction |
| title_fullStr | Inhibition of acyl‐CoA synthetase long‐chain isozymes decreases multiple myeloma cell proliferation and causes mitochondrial dysfunction |
| title_full_unstemmed | Inhibition of acyl‐CoA synthetase long‐chain isozymes decreases multiple myeloma cell proliferation and causes mitochondrial dysfunction |
| title_short | Inhibition of acyl‐CoA synthetase long‐chain isozymes decreases multiple myeloma cell proliferation and causes mitochondrial dysfunction |
| title_sort | inhibition of acyl coa synthetase long chain isozymes decreases multiple myeloma cell proliferation and causes mitochondrial dysfunction |
| topic | ACSL cell metabolism fatty acid hematological malignancies multiple myeloma Triacsin C |
| url | https://doi.org/10.1002/1878-0261.13794 |
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