Disruption of the unfolded protein response (UPR) by lead compound selectively suppresses cancer cell growth.
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| Abstract |
Identifying chemotherapy candidates with high selectivity against cancer cells is a major challenge in cancer treatment. Tumor microenvironments cause chronic endoplasmic reticulum (ER) stress and activate the unfolded protein response (UPR) as an adaptive response. Here, one novel small-molecule compound, 17#, was discovered as a potent pan-UPR inhibitor. It exhibited good selection for growth inhibition when cancer cells were cultured in 2-deoxy-D-glucose (2DG), mimicking an in vitro glucose-deprived status. Additionally, 17# alone could mildly suppress the growth of HeLa tumor xenografts, and a synergistic anti-cancer effect was observed when 17# was combined with 2DG. A mechanistic study showed that 17#-induced selective anti-cancer effects were highly dependent on UPR inhibition, and overexpressing GRP78 or XBP1s reversed the 17#-induced growth inhibition and cell cycle arrest, partially by delaying the downregulation of the cell cycle regulator cyclin B1. Furthermore, 17# improved the sensitivity of anti-cancer drugs such as doxorubicin or etoposide. Our study presents evidence that disrupting the UPR has selective therapeutic potential and may enhance drug sensitivity.
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| Authors | Hejing Huang, Huanan Liu, Changmei Liu, Lixia Fan, Xinwen Zhang, Anhui Gao, Xiaobei Hu, Kunzhi Zhang, Xianchao Cao, Kailong Jiang, Yubo Zhou, Jian Hou, Fajun Nan, Jia Li |
| Journal | Cancer letters (Cancer Lett) Vol. 360 Issue 2 Pg. 257-68 (May 01 2015) ISSN: 1872-7980 [Electronic] Ireland |
| PMID | 25721085 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
| Copyright | Copyright © 2015 Elsevier Ireland Ltd. All rights reserved. |
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