Clinical cancer research : an official journal of the American Association for Cancer Research · 2025
Targeting Acetyl-CoA Carboxylase Suppresses De Novo Lipogenesis and Tumor Cell Growth in Multiple Myeloma.
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Morelli Eugenio, Ribeiro Caroline Fidalgo, Rodrigues Silvia D, Gao Claire, Socciarelli Fabio, Maisano Domenico, Favasuli Vanessa, Liu Na, Todoerti Katia, Chakraborty Chandraditya, Yao Yao, Fulciniti Mariateresa, Samur Mehmet, Aktas-Samur Anil, Amodio Nicola, Turi Marcello, Barello Francesca, Penailillo Johany, Giallongo Cesarina, Romano Alessandra, Gulla Annamaria, Anderson Kenneth C, Inghirami Giorgio, Munshi Nikhil C, Loda Massimo
Аннотация
PURPOSE: In multiple myeloma, tumor cells reprogram metabolic pathways to sustain growth and monoclonal immunoglobulin production. This study examines acetyl-CoA carboxylase 1 (ACC1), the enzyme driving the rate-limiting step in de novo lipogenesis, in multiple myeloma metabolic reprogramming, particularly in c-MYC (MYC)-driven subtypes.
EXPERIMENTAL DESIGN: ACC1 expression was evaluated across multiple myeloma genetic subgroups, focusing on MYC translocations. Functional studies using ACC1 inhibitors and genetic knockdown assessed multiple myeloma cell growth, lipid synthesis, and metabolic homeostasis in vitro and in vivo. The role of MYC overexpression in ACC1 sensitivity was examined, with palmitate rescue experiments. Lipidomic analysis and assessments of endoplasmic reticulum (ER) stress, protein translation, and oxidative damage elucidated underlying mechanisms.
RESULTS: ACC1 was overexpressed in MYC-translocated multiple myeloma. Its inhibition or knockdown reduced multiple myeloma cell growth in vitro and in vivo, particularly in MYC-overexpressing cells. ACC1 knockdown suppressed de novo lipid synthesis, partially rescued by palmitate. Lipidomic disruptions increased cholesterol ester desaturation and altered phospholipid ratios, inducing ER stress, impaired translation, protein carbonylation, oxidative damage, and apoptosis.
CONCLUSIONS: ACC1 is a metabolic vulnerability in MYC-driven multiple myeloma. Inhibiting ACC1 disrupts lipid homeostasis, induces ER stress, and causes oxidative damage, impairing cell survival. Targeting lipid synthesis pathways, especially in MYC-dependent subtypes, offers a promising therapeutic strategy for multiple myeloma.
EXPERIMENTAL DESIGN: ACC1 expression was evaluated across multiple myeloma genetic subgroups, focusing on MYC translocations. Functional studies using ACC1 inhibitors and genetic knockdown assessed multiple myeloma cell growth, lipid synthesis, and metabolic homeostasis in vitro and in vivo. The role of MYC overexpression in ACC1 sensitivity was examined, with palmitate rescue experiments. Lipidomic analysis and assessments of endoplasmic reticulum (ER) stress, protein translation, and oxidative damage elucidated underlying mechanisms.
RESULTS: ACC1 was overexpressed in MYC-translocated multiple myeloma. Its inhibition or knockdown reduced multiple myeloma cell growth in vitro and in vivo, particularly in MYC-overexpressing cells. ACC1 knockdown suppressed de novo lipid synthesis, partially rescued by palmitate. Lipidomic disruptions increased cholesterol ester desaturation and altered phospholipid ratios, inducing ER stress, impaired translation, protein carbonylation, oxidative damage, and apoptosis.
CONCLUSIONS: ACC1 is a metabolic vulnerability in MYC-driven multiple myeloma. Inhibiting ACC1 disrupts lipid homeostasis, induces ER stress, and causes oxidative damage, impairing cell survival. Targeting lipid synthesis pathways, especially in MYC-dependent subtypes, offers a promising therapeutic strategy for multiple myeloma.