Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 510060, Guangzhou, China.
Department of Biochemistry and Molecular Biology, Zhongshan School of Medicine, Sun Yat-Sen University, 510080, Guangzhou, China.
Oncogene. 2018 Nov;37(46):6025-6040. doi: 10.1038/s41388-018-0384-z. Epub 2018 Jul 11.
Anoikis is a critical obstacle to cancer metastasis. Colorectal cancer (CRC) exhibits a high rate of metastasis, leading to death, and the mechanisms involved in anoikis resistance are still unclear. We identified that the fatty acid oxidation (FAO) pathway was activated in detached CRC cells. Multiple genes in the FAO pathway, specifically the rate-limiting enzyme CPT1A, were upregulated in CRC cells grown in suspension. Reactive oxygen species elimination mediated by CPT1A in CRC cells was vital to anoikis resistance. In vivo experiments showed that CPT1A-suppressed CRC cells colonized the lung at a much lower rate than normal CRC cells, suggesting that CPT1A-mediated FAO activation increased metastatic capacity. In clinical tissue specimens from CRC patients, elevated expression of CPT1A was observed in metastatic sites compared with primary sites. Our results demonstrate that CPT1A-mediated FAO activation induces CRC cells to resist anoikis, suggesting that CPT1A is an attractive target for treating metastatic CRC.
失巢凋亡是癌症转移的一个关键障碍。结直肠癌（CRC）表现出较高的转移率，导致死亡，而涉及失巢凋亡抵抗的机制尚不清楚。我们发现脂肪酸氧化（FAO）途径在分离的 CRC 细胞中被激活。FAO 途径中的多个基因，特别是限速酶 CPT1A，在悬浮培养的 CRC 细胞中上调。CPT1A 在 CRC 细胞中消除活性氧对于抗失巢凋亡至关重要。体内实验表明，CPT1A 抑制的 CRC 细胞在肺部定植的速度远低于正常 CRC 细胞，表明 CPT1A 介导的 FAO 激活增加了转移能力。在 CRC 患者的临床组织标本中，与原发部位相比，转移部位观察到 CPT1A 的表达升高。我们的结果表明，CPT1A 介导的 FAO 激活诱导 CRC 细胞抵抗失巢凋亡，表明 CPT1A 是治疗转移性 CRC 的一个有吸引力的靶点。
