Discovery of (4-bromophenyl)(3-hydroxy-4-methoxyphenyl)methanone through upregulating hTERT induces cell apoptosis and ERS View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2017-08-24

AUTHORS

Xiu Cheng, Jing Bo Shi, Hao Liu, Liu Zeng Chen, Yang Wang, Wen Jian Tang, Xin Hua Liu

ABSTRACT

Dominant-negative mutants of telomerase hTERT were demonstrated to have selective effects in tumor cells. However, no any effective and highly selective hTERT inhibitor has been developed so far. We focused on developing new hTERT modulators and synthesized a small molecular compound, named (4-bromophenyl)(3-hydroxy-4-methoxyphenyl)methanone. Our in vitro studies found that title compound showed high inhibitory activity against telomerase, had high antiproliferative capacity on SMMC-7721 cells with IC50 value 88 nm, and had no obvious toxic effect on human normal hepatocyte cells with IC50 value 10 μM. Our in vivo studies showed that this compound significantly inhibited tumor growth in xenograft tumor models. The further molecular mechanisms of title compound inhibition SMMC-7721 cell proliferation by modulating hTERT were explored; the results showed that endoplasmic reticulum stress (ERS) through ER over response (EOR) activates the expression of hTERT, and then induces ERS, which is believed to be intricately associated with oxidative stress and mitochondrial dysfunction, resulting in apoptotic cell death, thereby modulating the expression of downstream signaling molecules including CHOP (CAAT/enhancer-binding protein homologous protein)) and mitochondrion pathway of apoptosis, leading to inhibition of cell proliferation. More... »

PAGES

e3016

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/cddis.2017.384

DOI

http://dx.doi.org/10.1038/cddis.2017.384

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1091329589

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/28837145


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