Li Jiahao, Xian Ruiting, Li Rong
Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
Nan Fang Yi Ke Da Xue Xue Bao. 2025 Jun 20;45(6):1163-1173. doi: 10.12122/j.issn.1673-4254.2025.06.06.
To investigate the effect of downregulation of medium-chain acyl-coenzyme A dehydrogenase (ACADM) on invasion and migration of estrogen receptor-positive breast cancer cells and the underlying mechanism.
The Kaplan-Meier Plotter database was used to analyze the ACADM expression levels in breast cancer and normal tissues and their association with patient prognosis. Human breast cancer MCF-7 and T47D cell lines with lentivirus-mediated ACADM knockdown were established, and their in situ tumor formation and metastasis after tail vein injection were evaluated in nude mice. The MCF-7 and T47D cells with ACADM knockdown and their unmodified parental cells were examined with oil-red O staining assay, ROS assay, mitochondrial respiratory chain function assay before and after treatments with ROS scavenger, Elamipretide (a cardiolipin oxidation inhibitor) or SC79 (an AKT activator), and the changes in migration and invasion abilities of the treated cells were analyzed with Transwell invasion assay and Boyden chamber assay. Western blotting was used to detect protein expression levels of related signaling pathways in the treated cells.
ACADM overexpression was associated with a significantly shorter overall survival of breast cancer patients. In MCF-7 and T47D cells, ACADM knockdown resulted in downregulation of N calnexin, vimentin, p-P13K and p-AKT proteins, increased levels of free fatty acids and reactive oxygen species, lowered activities of mitochondrial respiratory chain complex III and V, and reduced mitochondrial inner phospholipids. ACADM knockdown significantly decreased the invasive capacity of the cells, which were obviously reversed by treatment with ROS scavenger, Elamipretide, and SC79.
Down-regulation of ACADM inhibits migration and invasion ability of estrogen receptor-positive breast cancer cells by lowering lipotoxicity and impairing mitochondrial function through the ROS/PI3K/AKT pathway.
探讨中链酰基辅酶A脱氢酶（ACADM）下调对雌激素受体阳性乳腺癌细胞侵袭和迁移的影响及其潜在机制。
利用Kaplan-Meier Plotter数据库分析乳腺癌组织和正常组织中ACADM的表达水平及其与患者预后的关系。建立慢病毒介导的ACADM敲低的人乳腺癌MCF-7和T47D细胞系，并在裸鼠中评估其尾静脉注射后的原位肿瘤形成和转移情况。对敲低ACADM的MCF-7和T47D细胞及其未修饰的亲本细胞进行油红O染色试验、活性氧（ROS）检测、线粒体呼吸链功能检测，在使用ROS清除剂、依拉米肽（一种心磷脂氧化抑制剂）或SC79（一种AKT激活剂）处理前后进行检测，并用Transwell侵袭试验和Boyden小室试验分析处理后细胞迁移和侵袭能力的变化。采用蛋白质印迹法检测处理后细胞中相关信号通路的蛋白表达水平。
ACADM过表达与乳腺癌患者的总生存期显著缩短有关。在MCF-7和T47D细胞中，ACADM敲低导致N钙连蛋白、波形蛋白、p-P13K和p-AKT蛋白表达下调，游离脂肪酸和活性氧水平升高，线粒体呼吸链复合体III和V的活性降低，线粒体内部磷脂减少。ACADM敲低显著降低了细胞的侵袭能力，而ROS清除剂、依拉米肽和SC79处理可明显逆转这种情况。
ACADM的下调通过降低脂毒性并通过ROS/PI3K/AKT途径损害线粒体功能，从而抑制雌激素受体阳性乳腺癌细胞的迁移和侵袭能力。
