Cholesterol Depletion by TASIN-1 Induces Apoptotic Cell Death through the ER Stress/ROS/JNK Signaling in Colon Cancer Cells

Lu Zhang, Sang Bum Kim, Krishna Luitel, Jerry W. Shay

Index: 10.1158/1535-7163.MCT-17-0887

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Abstract

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); 1–9. ©2018 AACR.