SLC44A2 negatively regulates mitochondrial fatty acid oxidation to suppress colorectal progression by blocking the MUL1-CPT2 interaction.

IF 8.1 1区 生物学 Q1 CELL BIOLOGY
Ying Yang, Longlong Zheng, Jiaxing He, Tao Wu, Haicheng Yang, Bo Zhang, Shuai Zhou, Yueyue Lu, Xianli He, Jibin Li, Nan Wang
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Abstract

The dependence of cancer cells on mitochondrial metabolism has been revealed in various cancer types. However, the mechanisms underlying this metabolic remodeling remain largely unclear. Solute carrier family 44 member 4 (SLC44A2) is a mitochondrial membrane-localized transmembrane protein belonging to the choline transporter-like protein family. Recently, it was reported that deletion of SLC44A2 impairs adhesion and increases proliferation in cultured lung mesenchymal cells. This finding implies that SLC44A2 may play a role in the malignant phenotypes of human cancers. However, the effects of SLC44A2 on malignant phenotypes and mitochondrial metabolism in human cancers remain unexplored. In the present investigation, we observed a significant reduction in SLC44A2 expression in colorectal cancer (CRC), and low SLC44A2 expression was closely associated with poorer survival of CRC patients. Functional assays demonstrated that SLC44A2 suppressed CRC growth and metastasis both in vitro and in vivo. Mechanistically, SLC44A2 inhibits mitochondrial fatty acid oxidation, thereby reducing energy supply and increase ROS stress. This effect is achieved by promoting mitochondrial E3 ubiquitin ligase 1 (MUL1)-regulated degradation of carnitine palmitoyltransferase 2 (CPT2) via enhancing the interaction between MUL1 and CPT2, without increasing MUL1 expression, which ultimately contributes to the proliferation and metastasis of CRC. Together, SLC44A2 functions as a critical tumor suppressor in CRC and potential therapeutic target in the treatment of this malignancy.

SLC44A2负调控线粒体脂肪酸氧化,通过阻断MUL1-CPT2相互作用抑制结直肠进展。
癌细胞对线粒体代谢的依赖性已在各种类型的癌症中得到揭示。然而,这种代谢重塑的机制在很大程度上仍不清楚。溶质载体家族44成员4 (SLC44A2)是一种线粒体膜定位的跨膜蛋白,属于胆碱转运蛋白家族。最近有报道称,SLC44A2的缺失会损害培养的肺间充质细胞的粘附并增加增殖。这一发现表明SLC44A2可能在人类癌症的恶性表型中发挥作用。然而,SLC44A2在人类癌症中对恶性表型和线粒体代谢的影响仍未被探索。在本研究中,我们观察到SLC44A2在结直肠癌(CRC)中的表达显著降低,SLC44A2的低表达与CRC患者较差的生存率密切相关。功能分析表明,SLC44A2在体内和体外均能抑制结直肠癌的生长和转移。在机制上,SLC44A2抑制线粒体脂肪酸氧化,从而减少能量供应,增加ROS应激。这一作用是通过增强线粒体E3泛素连接酶1 (MUL1)与CPT2之间的相互作用,促进线粒体E3泛素连接酶1 (MUL1)调控的肉毒碱palmitoyltransferase 2 (CPT2)的降解,而不增加MUL1的表达,最终导致CRC的增殖和转移。总之,SLC44A2在CRC中作为一个关键的肿瘤抑制因子和治疗这种恶性肿瘤的潜在治疗靶点。
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
Cell Death & Disease
Cell Death & Disease CELL BIOLOGY-
CiteScore
15.10
自引率
2.20%
发文量
935
审稿时长
2 months
期刊介绍: Brought to readers by the editorial team of Cell Death & Differentiation, Cell Death & Disease is an online peer-reviewed journal specializing in translational cell death research. It covers a wide range of topics in experimental and internal medicine, including cancer, immunity, neuroscience, and now cancer metabolism. Cell Death & Disease seeks to encompass the breadth of translational implications of cell death, and topics of particular concentration will include, but are not limited to, the following: Experimental medicine Cancer Immunity Internal medicine Neuroscience Cancer metabolism
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