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Title: Functional inhibition of the RNA ‐binding protein HuR sensitizes triple‐negative breast cancer to chemotherapy
Chemotherapy remains the standard treatment for triple‐negative breast cancer (TNBC); however, chemoresistance compromises its efficacy. The RNA‐binding protein Hu antigen R (HuR) could be a potential therapeutic target to enhance the chemotherapy efficacy. HuR is known to mainly stabilize its target mRNAs, and/or promote the translation of encoded proteins, which are implicated in multiple cancer hallmarks, including chemoresistance. In this study, a docetaxel‐resistant cell subline (231‐TR) was established from the human TNBC cell line MDA‐MB‐231. Both the parental and resistant cell lines exhibited similar sensitivity to the small molecule functional inhibitor of HuR, KH‐3. Docetaxel and KH‐3 combination therapy synergistically inhibited cell proliferation in TNBC cells and tumor growth in three animal models. KH‐3 downregulated the expression levels of HuR targets (e.g., β‐Catenin and BCL2) in a time‐ and dose‐dependent manner. Moreover, KH‐3 restored docetaxel's effects on activating Caspase‐3 and cleaving PARP in 231‐TR cells, induced apoptotic cell death, and caused S‐phase cell cycle arrest. Together, our findings suggest that HuR is a critical mediator of docetaxel resistance and provide a rationale for combining HuR inhibitors and chemotherapeutic agents to enhance chemotherapy efficacy.  more » « less
Award ID(s):
1943291
PAR ID:
10500777
Author(s) / Creator(s):
; ; ; ; ; ; ; ; ;
Publisher / Repository:
FEBS
Date Published:
Journal Name:
Molecular Oncology
Volume:
17
Issue:
10
ISSN:
1574-7891
Page Range / eLocation ID:
1962 to 1980
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
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