Truncated APC selective inhibitor-1 (TASIN-1) is a recently identified small molecule that selectively kills colorectal cancer cells that express truncated adenomatous polyposis coli (APC) by reducing cellular cholesterol levels. However, the downstream mechanism responsible for its cytotoxicity is not well understood. In this study, we show that TASIN-1 leads to apoptotic cell death via inducing ER stress-dependent JNK activation in human truncated APC colon cancer cells, accompanied by production of reactive oxygen species (ROS). In addition, TASIN-1 inhibits AKT activity through a cholesterol-dependent manner. Human colon tumor xenografts in immunodeficient mice also show the same TASIN-1 induced molecular mechanisms of tumor cell death as observed in vitro. Taken together, cholesterol depletion by TASIN-1 treatment induces apoptotic cell death through activating ER stress/ROS/JNK axis and inhibiting AKT pro-survival signaling in colon cancer cells with truncated APC both in vitro and in vivo. Mol Cancer Ther; 17(5); 943–51. ©2018 AACR.

中文翻译：

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TASIN-1 的胆固醇消耗通过结肠癌细胞中的内质网应激/ROS/JNK 信号传导诱导细胞凋亡

截短的 APC 选择性抑制剂-1 (TASIN-1) 是最近发现的一种小分子，可通过降低细胞胆固醇水平来选择性杀死表达截短的腺瘤性息肉病 (APC) 的结肠直肠癌细胞。然而，其细胞毒性的下游机制尚不清楚。在这项研究中，我们表明 TASIN-1 通过在人类截短的 APC 结肠癌细胞中诱导内质网应激依赖性 JNK 激活，伴随着活性氧 (ROS) 的产生而导致细胞凋亡。此外，TASIN-1 通过胆固醇依赖性方式抑制 AKT 活性。免疫缺陷小鼠中的人结肠肿瘤异种移植物也显示出与体外观察到的相同的 TASIN-1 诱导肿瘤细胞死亡的分子机制。综合起来，TASIN-1 处理导致的胆固醇消耗通过激活 ER 应激/ROS/JNK 轴并在体外和体内抑制具有截短 APC 的结肠癌细胞中的 AKT 促存活信号传导来诱导细胞凋亡。摩尔癌症治疗; 17(5); 943-51。©2018 AACR。