ACAA1 knockout increases the survival rate of KPC mice by activating autophagy

IF 6.6 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Molecular Metabolism Pub Date : 2025-08-21 DOI:10.1016/j.molmet.2025.102237

Ho Lee , Mingyu Kang , Sung Hoon Sim , Joon Hee Kang , Wonyoung Choi , Jung Won Chun , Woosol Hong , Chaeyoung Kim , Woojin Ham , Jeong Hwan Park , Eun-Byeol Koh , Yoon Jeon , Sang Myung Woo , Soo-Youl Kim

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引用次数: 0

Abstract

Objectives

We found that the levels of the peroxisomal fatty acid oxidation (FAO) marker in pancreatic ductal adenocarcinoma (PDAC) patients were higher than those in healthy individuals, based on tissue microarray analysis. This study investigates FAO in preclinical in vitro and in vivo models.

Methods

To examine the role of FAO in the peroxisome, we created acetyl-coenzyme A acyltransferase (ACAA1) knockout mice, crossed them with KPC mice, and monitored their survival rates. Additionally, we tested a mouse xenograft model with ACAA1 knockdown in human PDAC cells.

Results

In normal cells, ACAA1 knockdown did not affect oxygen consumption. In contrast, in PDAC cells, ACAA1 knockdown reduced the oxygen consumption rate by up to 60% and decreased ATP production by up to 70%. This suggests that peroxisomes in PDAC supply various acyl-carnitines for FAO in mitochondria. In PDAC cells, ACAA1 knockdown lowered ATP levels, resulting in mTOR inactivation and autophagy induction. Additionally, ACAA1 knockdown significantly increased LC3-II levels, leading to growth retardation in mouse xenograft models. Acaa1a^+/− mice showed a median survival increase of 3 weeks after crossing Acaa1a^+/− with KPC mice (Kras^G12D/+; Trp53^R172H/+; Pdx1-Cre, a genetically engineered mice model for PDAC).

Conclusions

ACAA1 knockdown inhibited tumor growth by triggering autophagy, which supported the survival of KPC mice. The most important benefit of targeting ACAA1 is that it blocks tumor growth specifically in cancer cells without harming normal cell energy metabolism.

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敲除ACAA1通过激活自噬提高KPC小鼠的存活率

目的：通过组织芯片分析，我们发现胰腺导管腺癌（PDAC）患者的过氧化物酶体脂肪酸氧化（FAO）标志物水平高于健康人群。本研究在体外和体内的临床前模型中研究了FAO。方法为了研究FAO在过氧化物酶体中的作用，我们建立了乙酰辅酶A酰基转移酶（ACAA1）敲除小鼠，将其与KPC小鼠杂交，并监测其存活率。此外，我们在人类PDAC细胞中测试了ACAA1敲低的小鼠异种移植模型。结果在正常细胞中，ACAA1基因敲低不影响耗氧量。相比之下，在PDAC细胞中，ACAA1敲低可使耗氧率降低高达60%，ATP产量降低高达70%。这表明PDAC中的过氧化物酶体为线粒体中的FAO提供各种酰基肉碱。在PDAC细胞中，ACAA1敲低降低ATP水平，导致mTOR失活和自噬诱导。此外，ACAA1敲低显著增加LC3-II水平，导致小鼠异种移植模型生长迟缓。Acaa1a+/−与KPC小鼠（KrasG12D/+; Trp53R172H/+; Pdx1-Cre，一种PDAC基因工程小鼠模型）杂交后，Acaa1a+/−小鼠的中位生存期增加了3周。结论acaa1基因敲低可通过触发自噬抑制肿瘤生长，支持KPC小鼠的存活。以ACAA1为靶点的最重要的好处是，它可以在不损害正常细胞能量代谢的情况下，特异性地阻断癌细胞中的肿瘤生长。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Metabolism ENDOCRINOLOGY & METABOLISM-

CiteScore

14.50

自引率

2.50%

发文量

219

审稿时长

43 days

期刊介绍： Molecular Metabolism is a leading journal dedicated to sharing groundbreaking discoveries in the field of energy homeostasis and the underlying factors of metabolic disorders. These disorders include obesity, diabetes, cardiovascular disease, and cancer. Our journal focuses on publishing research driven by hypotheses and conducted to the highest standards, aiming to provide a mechanistic understanding of energy homeostasis-related behavior, physiology, and dysfunction. We promote interdisciplinary science, covering a broad range of approaches from molecules to humans throughout the lifespan. Our goal is to contribute to transformative research in metabolism, which has the potential to revolutionize the field. By enabling progress in the prognosis, prevention, and ultimately the cure of metabolic disorders and their long-term complications, our journal seeks to better the future of health and well-being.