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Functional inhibition of the RNA‐binding protein HuR sensitizes triple‐negative breast cancer to chemotherapy
Wei, Lanjing Zhang, Qi Zhong, Cuncong He, Lily Zhang, Yuxia M. Armaly, Ahlam Aubé, Jeffrey R. Welch, Danny Xu, Liang Wu, Xiaoqing
Wei, Lanjing
Zhang, Qi
Zhong, Cuncong
He, Lily
Zhang, Yuxia
M. Armaly, Ahlam
Aubé, Jeffrey
R. Welch, Danny
Xu, Liang
Wu, Xiaoqing
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Abstract
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.
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2023-07-19
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FEBS PRESS
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MOL2-17-1962.pdf
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Keywords
Animal tumor model, Chemoresistance, Docetaxel, HuR, TNBC
Citation
Wei L, Zhang Q, Zhong C, He L, Zhang Y, Armaly AM, Aubé J, Welch DR, Xu L, Wu X. Functional inhibition of the RNA-binding protein HuR sensitizes triple-negative breast cancer to chemotherapy. Mol Oncol. 2023 Oct;17(10):1962-1980. doi: 10.1002/1878-0261.13478. Epub 2023 Jul 19. PMID: 37357618; PMCID: PMC10552894