Zhang Lu, Theodoropoulos Panayotis C, Eskiocak Ugur, Wang Wentian, Moon Young-Ah, Posner Bruce, Williams Noelle S, Wright Woodring E, Kim Sang Bum, Nijhawan Deepak, De Brabander Jef K, Shay Jerry W
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Sci Transl Med. 2016 Oct 19;8(361):361ra140. doi: 10.1126/scitranslmed.aaf8127.
Mutations in the adenomatous polyposis coli (APC) gene are common in colorectal cancer (CRC), and more than 90% of those mutations generate stable truncated gene products. We describe a chemical screen using normal human colonic epithelial cells (HCECs) and a series of oncogenically progressed HCECs containing a truncated APC protein. With this screen, we identified a small molecule, TASIN-1 (truncated APC selective inhibitor-1), that specifically kills cells with APC truncations but spares normal and cancer cells with wild-type APC. TASIN-1 exerts its cytotoxic effects through inhibition of cholesterol biosynthesis. In vivo administration of TASIN-1 inhibits tumor growth of CRC cells with truncated APC but not APC wild-type CRC cells in xenograft models and in a genetically engineered CRC mouse model with minimal toxicity. TASIN-1 represents a potential therapeutic strategy for prevention and intervention in CRC with mutant APC.
腺瘤性息肉病 coli（APC）基因的突变在结直肠癌（CRC）中很常见，超过90%的此类突变会产生稳定的截短基因产物。我们描述了一种使用正常人结肠上皮细胞（HCECs）和一系列含有截短APC蛋白的致癌进展HCECs进行的化学筛选。通过该筛选，我们鉴定出一种小分子TASIN-1（截短APC选择性抑制剂-1），它能特异性杀死具有APC截短的细胞，但对具有野生型APC的正常细胞和癌细胞无害。TASIN-1通过抑制胆固醇生物合成发挥其细胞毒性作用。在异种移植模型和基因工程CRC小鼠模型中，体内给予TASIN-1可抑制具有截短APC的CRC细胞的肿瘤生长，但对APC野生型CRC细胞无效，且毒性极小。TASIN-1代表了一种针对具有突变APC的CRC进行预防和干预的潜在治疗策略。
