Dikkatli Öykü Irmak, Cavlak Yunus Emre, Çakıl Yaprak Dönmez, Atılkan Sueda, Yurtcu Erkan, İşeri Özlem Darcansoy
Department of Molecular Biology and Genetics, Institute of Science, Başkent University, Ankara, Türkiye.
TENMAK, Boron Research Institute, Ankara, Türkiye.
J Biochem Mol Toxicol. 2025 Jul;39(7):e70397. doi: 10.1002/jbt.70397.
Zoledronic acid (ZA), a bisphosphonate derivate, became the standard for preserving bone structure in cancer. Using various intracellular signaling pathways, including NF-κB, ZA inhibits tumor cell proliferation, induces apoptosis, and has additive and synergistic effects with cytotoxic agents. However, it has been observed that resistance has developed against ZA. This study aims to explore the underlying mechanisms of ZA resistance in MCF-7 breast cancer cells by investigating the activity and localization of the human breast cancer resistance protein (BCRP), changes in the NF-κB pathway, and the markers of epithelial-mesenchymal transition (EMT). Previously, MCF-7 cells were stepwise selected in increasing concentrations of ZA and became resistant to 8 µM ZA (MCF-7/Zol). We determined that BCRP levels were elevated with altered intracellular localization in ZA resistant MCF-7 cells, and BCRP pump caused a decrease in the substrate accumulation in the MCF-7/Zol cells whereas no change in intercellular substrate accumulation was observed in parental cells. MCF-7/Zol cells have increased amount of phosphorylated IκB which is associated with increased nuclear translocation of NF-κB. Concordantly, BCRP upregulation may be associated with increased nuclear NF-κB in ZA resistant cells. MCF-7/Zol cells did not harbor EMT markers. Elucidation of molecular mechanisms of resistance developed against chemotherapeutic agents is important to target critical pathways and proteins to eliminate the resistant clones as well as for determining biomarkers for MDR.
唑来膦酸（ZA）是一种双膦酸盐衍生物，已成为癌症中维持骨结构的标准药物。ZA通过多种细胞内信号通路，包括核因子κB（NF-κB），抑制肿瘤细胞增殖、诱导凋亡，并与细胞毒性药物具有相加和协同作用。然而，已观察到对ZA产生了耐药性。本研究旨在通过研究人乳腺癌耐药蛋白（BCRP）的活性和定位、NF-κB通路的变化以及上皮-间质转化（EMT）标志物，探索MCF-7乳腺癌细胞中ZA耐药的潜在机制。此前，MCF-7细胞在逐渐增加浓度的ZA中进行逐步筛选，对8 μM ZA产生了耐药性（MCF-7/Zol）。我们确定，在ZA耐药的MCF-7细胞中，BCRP水平升高且细胞内定位改变，BCRP转运蛋白导致MCF-7/Zol细胞中底物积累减少，而在亲本细胞中未观察到细胞间底物积累的变化。MCF-7/Zol细胞中磷酸化IκB的量增加，这与NF-κB核转位增加有关。一致地，BCRP上调可能与ZA耐药细胞中核NF-κB增加有关。MCF-7/Zol细胞未携带EMT标志物。阐明对化疗药物产生耐药性的分子机制对于靶向关键通路和蛋白以消除耐药克隆以及确定多药耐药的生物标志物很重要。
