Wei Lanjing, Kim Sung Hae, Armaly Ahlam M, Aubé Jeffrey, Xu Liang, Wu Xiaoqing
Bioengineering Program, The University of Kansas, Lawrence, KS, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
NPJ Precis Oncol. 2024 Dec 20;8(1):286. doi: 10.1038/s41698-024-00780-x.
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.
三阴性乳腺癌（TNBC）由于靶向治疗选择有限且对化疗药物（如阿霉素）耐药，带来了治疗挑战。本研究调查了阿霉素耐药机制及克服该耐药性的策略。从MDA-MB-231三阴性乳腺癌细胞中培育出阿霉素耐药细胞亚系（231-DR），并确定231-DR细胞中细胞FLICE抑制蛋白（cFLIP）的表达增强是耐药的潜在驱动因素。cFLIP的过表达赋予了对阿霉素诱导的细胞凋亡的抗性，而小干扰RNA介导的cFLIP缺失则诱导了细胞凋亡，尤其是在231-DR细胞中。此外，发现RNA结合蛋白Hu抗原R（HuR）可调节cFLIP的表达。用KH-3或RNA干扰抑制HuR可降低cFLIP水平。重要的是，KH-3使三阴性乳腺癌细胞对阿霉素诱导的细胞凋亡敏感。总之，本研究阐述了cFLIP在介导阿霉素耐药中的作用，并确定HuR是cFLIP的正向调节因子，通过将HuR抑制与阿霉素联合使用，为对抗三阴性乳腺癌的化疗耐药性提供了一条新的治疗途径。
