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 vivoMol Cancer Ther; 17(5); 943-51. ©2018 AACR.
Highlights
Colorectal cancer (CRC) is the third most commonly diagnosed cancer and third leading cause of cancer-related mortality in the United States
D, Cleaved PARP was determined by Western blot analysis in HCT116 and DLD1 cells treated with 2.5 mmol/L of truncated adenomatous polyposis coli (APC) selective inhibitor-1 (TASIN-1) for 24, 48, or 60 hours in HCEC media with 0.2% serum. b-Actin was used as loading control
F, Cleaved PARP was determined by Western blot analysis in HCT116 and DLD1 cells treated as described in E. b-Actin was used as loading control
Summary
Colorectal cancer (CRC) is the third most commonly diagnosed cancer and third leading cause of cancer-related mortality in the United States. Mutation in the adenomatous polyposis coli (APC) tumor suppressor gene is a frequent and early, if not initiating, event in colorectal cancer tumorigenesis [2, 3]. We identified a small molecule, truncated APC selective inhibitor-1 (TASIN-1), that is toxic to truncated APC CRC cells while sparing normal and other cancer cells expressing wild-type APC [5, 6]. This compound induces cell death through depletion of cholesterol in truncated APC cells [6]. The downstream mechanism in response to TASIN-1–induced cholesterol depletion remains to be determined
Sign-in/Register to view highlights & summary 
Submitted Version (
Free)
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call