The Regulators of Peroxisomal Acyl-Carnitine Shuttle CROT and CRAT Promote Metastasis in Melanoma
The Regulators of Peroxisomal Acyl-Carnitine Shuttle CROT and CRAT Promote Metastasis in Melanoma
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DOI：
10.1016/j.jid.2022.08.038
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发表时间：
2023-01-19
影响因子：
6.5
通讯作者：
Arozarena, Imanol
中科院分区：
文献类型：
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作者：
Lasheras-Otero, Irene;Feliu, Iker;Arozarena, Imanol
循环肿瘤细胞是原发性肿瘤和远处转移之间的关键环节，但一旦进入血流，粘附力的丧失会诱导细胞死亡。为了确定与黑色素瘤循环肿瘤细胞存活相关的机制，我们进行了RNA测序，发现分离的黑色素瘤细胞和分离的黑色素瘤循环肿瘤细胞通过上调脂肪酸（FA）转运和FA β-氧化相关基因来重塑脂质代谢。在黑色素瘤患者中，FA转运蛋白和FA β-氧化酶的高表达与无进展生存期和总生存期降低显著相关。在黑色素瘤循环肿瘤细胞中表达最高的调节剂是肉毒碱转移酶肉毒碱O-辛酰基转移酶和肉毒碱乙酰转移酶，其控制过氧化物酶体衍生的中链FA向线粒体的穿梭以促进线粒体FA β氧化。在小鼠中，肉毒碱O-辛酰基转移酶或肉毒碱乙酰转移酶的敲低和过氧化物酶体或线粒体FA β-氧化抑制剂硫利达嗪或雷诺嗪的短期治疗抑制了黑色素瘤转移。肉毒碱O-辛酰基转移酶和肉毒碱乙酰转移酶消耗可以通过中链FA补充剂来拯救，这表明FA的过氧化物酶体供应对于非粘附性黑色素瘤细胞的生存至关重要。我们的研究确定了针对过氧化物酶体和线粒体之间基于FA的串扰作为挑战黑色素瘤进展的潜在治疗机会。此外，美国食品和药物管理局批准的药物雷诺嗪的抗转移活性的发现具有转化潜力。
Circulating tumor cells are the key link between a primary tumor and distant metastases, but once in the bloodstream, loss of adhesion induces cell death. To identify the mechanisms relevant for melanoma circulating tumor cell survival, we performed RNA sequencing and discovered that detached melanoma cells and isolated melanoma circulating tumor cells rewire lipid metabolism by upregulating fatty acid (FA) transport and FA beta-oxidation-related genes. In patients with melanoma, high expression of FA transporters and FA beta-oxidation enzymes significantly correlates with reduced progression-free and overall survival. Among the highest expressed regulators in melanoma circulating tumor cells were the carnitine transferases carnitine O-octanoyl-transferase and carnitine acetyltransferase, which control the shuttle of peroxisome-derived medium-chain FAs toward mitochondria to fuel mitochondrial FA beta-oxidation. Knockdown of carnitine O-octanoyltransferase or carnitine acetyltransferase and short-term treatment with peroxisomal or mitochondrial FA beta-oxidation in-hibitors thioridazine or ranolazine suppressed melanoma metastasis in mice. Carnitine O-octanoyltransferase and carnitine acetyltransferase depletion could be rescued by medium-chain FA supplementation, indicating that the peroxisomal supply of FAs is crucial for the survival of nonadherent melanoma cells. Our study identifies targeting the FA-based cross-talk between peroxisomes and mitochondria as a potential therapeutic opportunity to challenge melanoma progression. Moreover, the discovery of the antimetastatic activity of the Food and Drug Administration-approved drug ranolazine carries translational potential.