In:
British Journal of Pharmacology, Wiley, Vol. 171, No. 17 ( 2014-09), p. 4010-4025
Abstract:
YC ‐1 exhibits potent anticancer activity via numerous actions in many cancer cell lines. Hence, we investigated the in vivo antitumour efficacy of YC ‐1 in an MDA‐MB ‐468 xenograft model and elucidated the mechanism of down‐regulation of enhancer of zeste homology 2 ( EZH 2) by YC ‐1 in breast cancer cells. Experimental Approach In YC –1‐treated breast cancer cells and tumour specimens from YC –1‐treated MDA‐MB ‐468 xenografts, EZH 2 expression was analysed by W estern blotting. Pharmacological inhibitors and short hairpin RNA ‐mediated knockdown were applied to identify possible signalling pathways involved in EZH 2 down‐regulation by YC ‐1. Key Results YC ‐1 reduced the viability of breast cancer cells and tumour growth in MDA‐MB ‐468 xenografts. In breast cancer cells, YC ‐1 down‐regulated EZH 2 expression in a concentration‐ and time‐dependent manner. Depletion of EZH 2 reduced the proliferation and susceptibility of breast cancer cells to YC –1‐induced apoptosis. EZH 2 expression was suppressed in tumour specimens from YC –1‐treated MDA‐MB ‐468 xenograft mice. YC‐1 enhanced both the degradation rate and ubiquitination of EZH 2. The down‐regulation of EZH 2 by YC ‐1 was associated with activation of PKA and S rc– R af– ERK ‐mediated signalling pathways. Furthermore, depletion of C asitas B ‐lineage lymphoma (c‐ C bl), an E 3 ubiquitin ligase, abolished YC –1‐induced apoptosis and suppression of EZH 2. YC ‐1 rapidly activated c‐ C bl to induce signalling associated with ERK and EZH 2. Conclusion and Implications We discovered that YC ‐1 induces apoptosis and inhibits tumour growth of breast cancer cells via down‐regulation of EZH 2 by activating c‐ C bl and ERK . These data suggest that YC ‐1 is a potential anticancer drug candidate for triple‐negative breast cancer.
Type of Medium:
Online Resource
ISSN:
0007-1188
,
1476-5381
DOI:
10.1111/bph.2014.171.issue-17
Language:
English
Publisher:
Wiley
Publication Date:
2014
detail.hit.zdb_id:
2029728-2
SSG:
15,3
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