HuR inhibition overcomes cFLIP-mediated doxorubicin resistance in triple-negative breast cancer

作者：Lanjing Wei, Sung Hae Kim, Ahlam M. Armaly, Jeffrey Aubé, Liang Xu, Xiaoqing Wu · 发表于：npj Precision Oncology · 年份：2024 · DOI：10.1038/s41698-024-00780-x · 被引用次数：10 · 研究领域：RNA Research and Splicing、RNA modifications and cancer、Cancer-related molecular mechanisms research

Triple-negative breast cancer (TNBC) presents therapeutic challenges due to limited targeted treatment options and resistance to chemotherapy drugs, such as doxorubicin. This study investigated doxorubicin resistance mechanisms and a strategy to overcome it. A doxorubicin-resistant cell subline (231-DR) was developed from MDA-MB-231 TNBC cells, and enhanced expression of cellular FLICE-inhibitory protein (cFLIP) in 231-DR cells was identified as a potential driver of the resistance. Overexpression of cFLIP conferred resistance to doxorubicin-induced apoptosis, whereas siRNA-mediated cFLIP depletion induced apoptosis, particularly in 231-DR cells. Furthermore, the RNA-binding protein Hu antigen R (HuR) was found to regulate cFLIP expression. HuR Inhibition with KH-3 or RNA interference reduced cFLIP levels. Importantly, KH-3 sensitized TNBC cells to doxorubicin-induced apoptosis. In summary, this study delineates cFLIP's role in mediating doxorubicin resistance and identifies HuR as a positive regulator of cFLIP, offering a novel therapeutic avenue against chemoresistance in TNBC by combining HuR inhibition with doxorubicin.