Colorectal cancer (CRC) is one of the most common malignancies worldwide, and effective therapy remains a challenge. In this study, we take advantage of a drug repurposing strategy to screen small molecules with novel anticancer activities in a small-molecule library consisting of 1056 FDA-approved drugs. We show, for the first time, that lomitapide, a lipid-lowering agent, exhibits antitumor properties in vitro and in vivo. Activated autophagy is characterized as a key biological process in lomitapide-induced CRC repression. Mechanistically, lomitapide stimulated mitochondrial dysfunction-mediated AMPK activation, resulting in increased AMPK phosphorylation and enhanced Beclin1/Atg14/Vps34 interactions, provoking autophagy induction. Autophagy inhibition or AMPK silencing significantly abrogated lomitapide-induced cell death, indicating the significance of AMPK-regulated autophagy in the antitumor activities of lomitapide. More importantly, PP2A was identified as a direct target of lomitapide by limited proteolysis-mass spectrometry (LiP-SMap), and the bioactivity of lomitapide was attenuated in PP2A-deficient cells, suggesting that the anticancer effect of lomitapide occurs in a PP2A-dependent manner. Taken together, the results of the study reveal that lomitapide can be repositioned as a potential therapeutic drug for CRC treatment.

结直肠癌 (CRC) 是全球最常见的恶性肿瘤之一，有效的治疗仍然是一个挑战。在这项研究中，我们利用药物再利用策略在由 1056 种 FDA 批准的药物组成的小分子库中筛选具有新型抗癌活性的小分子。我们首次证明洛美他派是一种降脂剂，在体外和体内都具有抗肿瘤特性. 激活的自噬被表征为洛美他派诱导的 CRC 抑制的关键生物学过程。从机制上讲，lomitapide 刺激线粒体功能障碍介导的 AMPK 激活，导致 AMPK 磷酸化增加和 Beclin1/Atg14/Vps34 相互作用增强，引发自噬诱导。自噬抑制或 AMPK 沉默显着消除了洛美他派诱导的细胞死亡，表明 AMPK 调节的自噬在洛美他派的抗肿瘤活性中具有重要意义。更重要的是，PP2A 被有限蛋白水解质谱（LiP-SMap）鉴定为洛美他派的直接靶点，洛美他派的生物活性在 PP2A 缺陷细胞中减弱，表明洛美他派的抗癌作用发生在 PP2A 依赖性细胞中。方式。综合起来，