Decoding Potassium Homeostasis in Cancer Metastasis and Drug Resistance: Insights from a Highly Selective DNAzyme-Based Intracellular K+ Sensor

作者：Zhenglin Yang, Xiangli Shao, Yuting Wu, Aritra Roy, Edwin García, A. P. Farrell, Subhashree Pradhan, Weijie Guo, Heather Gan, Zeynep Korkmaz, Emily J. Adams, Yi Lu · 发表于：Journal of the American Chemical Society · 年份：2025 · DOI：10.1021/jacs.5c03781 · 被引用次数：8 · 研究领域：Advanced biosensing and bioanalysis techniques、Molecular Sensors and Ion Detection、Analytical Chemistry and Sensors

Potassium ions (K + ) within the tumor microenvironment, along with dysregulation of K + channels, play critical roles in supporting cancer cell survival and preventing their elimination. Directly monitoring changes in K + homeostasis within cancer cells is invaluable for understanding these processes. However, achieving high selectivity over other biological metal ions, a detection dynamic range that aligns with intracellular K + levels, and broad accessibility to research laboratories remain technically challenging for current K + imaging probes. In this study, we report the in vitro selection of the first K + -specific RNA-cleaving DNAzyme and the development of a K + -specific DNAzyme fluorescent sensor with exceptional selectivity, achieving over 1000-fold selectivity against Na + and more than 100-fold selectivity over other major biologically relevant metal ions. This sensor has an apparent dissociation constant (105 mM) that is close to the intracellular level of K +, and it has a broad detection range from 21 to 200 mM K + . Using this tool, we reveal a progressive decline in intracellular K + levels in breast cancer cells with more advanced progression states. Moreover, we demonstrate that elevated extracellular K + levels interfere with the efficacy of anticancer compounds like ML133 and Amiodarone, suggesting an underappreciated role of microenvironmental K + in chemoresistance. Notably, blocking the Kir2.1 channel activity restored treatment sensitivity, presenti...