ACSS1-dependent acetate utilization rewires mitochondrial metabolism to support AML and melanoma tumor growth and metastasis.

IF 7.5 1区生物学 Q1 CELL BIOLOGY Cell reports Pub Date : 2024-11-21 DOI:10.1016/j.celrep.2024.114988

Sabina I Hlavaty, Kelsey N Salcido, Katherine A Pniewski, Dzmitry Mukha, Weili Ma, Toshitha Kannan, Joel Cassel, Yellamelli V V Srikanth, Qin Liu, Andrew Kossenkov, Joseph M Salvino, Qing Chen, Zachary T Schug

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Abstract

Cancer cells often use alternative nutrient sources to support their metabolism and proliferation. One important alternative nutrient source for many cancers is acetate. Acetate is metabolized into acetyl-coenzyme A (CoA) by acetyl-CoA synthetases 1 and 2 (ACSS1 and ACSS2), which are found in the mitochondria and cytosol, respectively. We show that ACSS1 and ACSS2 are differentially expressed in cancer. Melanoma, breast cancer, and acute myeloid leukemia cells expressing ACSS1 readily use acetate for acetyl-CoA biosynthesis and to fuel mitochondrial metabolism. ACSS1-dependent acetate metabolism decreases the relative contributions of glucose and glutamine to the tricarboxylic acid (TCA) cycle and alters the pentose phosphate pathway and redox state of cancer cells. ACSS1 knockdown decreases acute myeloid leukemia burden in vivo and inhibits melanoma tumor and metastatic growth. Our study highlights a key role for ACSS1-dependent acetate metabolism for cancer growth, raising the potential for ACSS1-targeting therapies in cancer.

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依赖 ACSS1 的醋酸利用重新构建线粒体代谢，支持急性髓细胞白血病和黑色素瘤的生长和转移。

癌细胞通常使用替代营养源来支持其新陈代谢和增殖。醋酸是许多癌症的重要替代营养源之一。乙酸通过乙酰辅酶 A 合成酶 1 和 2（ACSS1 和 ACSS2）代谢为乙酰辅酶 A（CoA），它们分别存在于线粒体和细胞质中。我们发现 ACSS1 和 ACSS2 在癌症中有不同的表达。表达 ACSS1 的黑色素瘤、乳腺癌和急性髓性白血病细胞很容易将乙酸酯用于乙酰-CoA 的生物合成和线粒体代谢。依赖 ACSS1 的乙酸代谢会降低葡萄糖和谷氨酰胺对三羧酸（TCA）循环的相对贡献，并改变磷酸戊糖途径和癌细胞的氧化还原状态。敲除 ACSS1 可减少急性髓性白血病的体内负担，抑制黑色素瘤的肿瘤和转移生长。我们的研究强调了依赖 ACSS1 的醋酸代谢对癌症生长的关键作用，从而提高了 ACSS1 靶向疗法治疗癌症的潜力。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.