Identification of Small Molecules That Protect Pancreatic 尾 Cells against Endoplasmic Reticulum Stress-Induced Cell Death
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- 作者：Kim Tran ; Yu Li ; Hongliang Duan ; Daleep Arora ; Hui-Ying Lim ; Weidong Wang
- 刊名：ACS Chemical Biology
- 出版年：2014
- 出版时间：December 19, 2014
- 年：2014
- 卷：9
- 期：12
- 页码：2796-2806
- 全文大小：654K
- ISSN：1554-8937
文摘
Endoplasmic reticulum (ER) stress plays an important role in the decline in pancreatic 尾 cell function and mass observed in type 2 diabetes. Here, we developed a novel 尾 cell-based high-throughput screening assay to identify small molecules that protect 尾 cells against ER stress-induced cell death. Mouse 尾TC6 cells were treated with the ER stressor tunicamycin to induce ER stress, and cell death was measured as a reduction in cellular ATP. A collection of 17600 compounds was screened for molecules that promote 尾 cell survival. Of the approximately 80 positive hits, two selected compounds were able to increase the survival of human primary 尾 cells and rodent 尾 cell lines subjected to ER stressors including palmitate, a free fatty acid of pathological relevance to diabetes. These compounds also restored ER stress-impaired glucose-stimulated insulin secretion responses. We show that the compounds promote 尾 cell survival by reducing the expression of key genes of the unfolded protein response and apoptosis, thus alleviating ER stress. Identification of small molecules that prevent ER stress-induced 尾 cell dysfunction and death may provide a new modality for the treatment of diabetes.