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
Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy.
Department of Oncology, University of Torino, Candiolo, Italy.
Clin Cancer Res. 2025 May 15;31(10):1975-1987. doi: 10.1158/1078-0432.CCR-24-2000.
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.
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.
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.
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.
在多发性骨髓瘤中，肿瘤细胞会重新编程代谢途径以维持生长和单克隆免疫球蛋白的产生。本研究检测了在多发性骨髓瘤代谢重编程中，尤其是在c-MYC（MYC）驱动的亚型中，作为从头脂肪生成限速步骤驱动酶的乙酰辅酶A羧化酶1（ACC1）。
在多发性骨髓瘤基因亚组中评估ACC1的表达，重点关注MYC易位情况。使用ACC1抑制剂和基因敲低进行的功能研究评估了体外和体内多发性骨髓瘤细胞的生长、脂质合成和代谢稳态。通过棕榈酸挽救实验研究了MYC过表达在ACC1敏感性中的作用。脂质组学分析以及对内质网（ER）应激、蛋白质翻译和氧化损伤的评估阐明了潜在机制。
ACC1在MYC易位的多发性骨髓瘤中过表达。其抑制或敲低可降低体外和体内多发性骨髓瘤细胞的生长，尤其是在MYC过表达的细胞中。ACC1敲低抑制了从头脂质合成，棕榈酸可部分挽救该作用。脂质组学紊乱增加了胆固醇酯去饱和并改变了磷脂比例，诱导了ER应激、翻译受损、蛋白质羰基化、氧化损伤和细胞凋亡。
ACC1是MYC驱动的多发性骨髓瘤中的一种代谢弱点。抑制ACC1会破坏脂质稳态，诱导ER应激并导致氧化损伤，损害细胞存活。靶向脂质合成途径，尤其是在MYC依赖的亚型中，为多发性骨髓瘤提供了一种有前景的治疗策略。
