Yamashita Miho, Tsukamoto Megumi, Imai Ritsuko, Muramatsu Himari, Nakagawa Hiroshi
Department of Applied Biological Chemistry, Graduate School of Bioscience and Biotechnology, Chubu University, 1200 Matsumoto-cho, Kasugai 487-8501, Japan.
Department of Applied Biological Chemistry, College of Bioscience and Biotechnology, Chubu University, 1200 Matsumoto-cho, Kasugai 487-8501, Japan.
Int J Mol Sci. 2025 Aug 1;26(15):7428. doi: 10.3390/ijms26157428.
The ATP-binding cassette transporter ABCG2 plays a critical role in drug pharmacokinetics and multidrug resistance in cancer therapy. Two common nonsynonymous polymorphisms, rs2231137 (V12M) and rs2231142 (Q141K), are associated with altered ABCG2 function, drug response, and disease susceptibility. However, the functional impact of their haplotype remains poorly understood. In this study, we established Flp-In™-293 cell lines stably expressing ABCG2 (12M/141K) and systematically compared their expression and drug resistance profiles with those of cells expressing ABCG2 (12V/141Q) (WT), ABCG2 (12M/141Q), and ABCG2 (12V/141K). The mRNA of ABCG2 (12M/141K) was expressed at levels comparable to those of the other variants in cells. Cells expressing ABCG2 (12M/141K) exhibited significantly higher resistance to mitoxantrone (10.7-fold) and SN-38 (5.99-fold) than the mock cells. While ABCG2 (12M/141Q) conferred the highest resistance among the tested variants, the haplotype showed a trend toward higher mitoxantrone resistance than the ABCG2 (12V/141Q) (WT) ( = 0.066), suggesting a haplotype-specific effect. These findings provide novel insights into haplotype-based modulation of ABCG2 function and its contribution to multidrug resistance, with potential implications for optimizing personalized chemotherapy strategies.
ATP结合盒转运体ABCG2在药物药代动力学和癌症治疗中的多药耐药性方面发挥着关键作用。两种常见的非同义多态性，即rs2231137（V12M）和rs2231142（Q141K），与ABCG2功能改变、药物反应及疾病易感性相关。然而，它们单倍型的功能影响仍知之甚少。在本研究中，我们建立了稳定表达ABCG2（12M/141K）的Flp-In™-293细胞系，并系统地将其表达和耐药谱与表达ABCG2（12V/141Q）（野生型）、ABCG2（12M/141Q）和ABCG2（12V/141K）的细胞进行了比较。ABCG2（12M/141K）的mRNA在细胞中的表达水平与其他变体相当。与mock细胞相比，表达ABCG2（12M/141K）的细胞对米托蒽醌（10.7倍）和SN-38（5.99倍）表现出显著更高的耐药性。虽然ABCG2（12M/141Q）在所测试的变体中耐药性最高，但该单倍型对米托蒽醌的耐药性比ABCG2（12V/141Q）（野生型）有升高趋势（P = 0.066），提示存在单倍型特异性效应。这些发现为基于单倍型的ABCG2功能调节及其对多药耐药性的贡献提供了新见解，对优化个性化化疗策略具有潜在意义。
