Department of Biotechnology and Bioindustry Sciences, National Cheng Kung University, Tainan, Taiwan.
School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Cell Death Differ. 2021 Sep;28(9):2690-2707. doi: 10.1038/s41418-021-00778-z. Epub 2021 Apr 12.
Drug resistance has remained an important issue in the treatment and prevention of various diseases, including cancer. Herein, we found that USP24 not only repressed DNA-damage repair (DDR) activity by decreasing Rad51 expression to cause the tumor genomic instability and cancer stemness, but also increased the levels of the ATP-binding cassette (ABC) transporters P-gp, ABCG2, and ezrin to enhance the pumping out of Taxol from cancer cells, thus resulted in drug resistance during cancer therapy. A novel USP24 inhibitor, NCI677397, was screened for specific inhibiting the catalytic activity of USP24. This inhibitor was identified to suppress drug resistance via decreasing genomic instability, cancer stemness, and the pumping out of drugs from cancer cells. Understanding the role and molecular mechanisms of USP24 in drug resistance will be beneficial for the future development of a novel USP24 inhibitor. Our studies provide a new insight of USP24 inhibitor for clinically implication of blocking drug resistance during chemotherapy.
耐药性一直是各种疾病（包括癌症）治疗和预防的重要问题。在这里，我们发现 USP24 不仅通过降低 Rad51 表达来抑制 DNA 损伤修复（DDR）活性，导致肿瘤基因组不稳定和癌症干性，还增加了 ABC 转运蛋白 P-糖蛋白、ABCG2 和 ezrin 的水平，以增强紫杉醇从癌细胞中泵出，从而导致癌症治疗过程中的耐药性。我们筛选了一种新型 USP24 抑制剂 NCI677397，用于特异性抑制 USP24 的催化活性。该抑制剂通过降低基因组不稳定性、癌症干性和癌细胞中药物的泵出作用来抑制耐药性。了解 USP24 在耐药性中的作用和分子机制将有助于未来开发新型 USP24 抑制剂。我们的研究为临床应用 USP24 抑制剂阻断化疗过程中的耐药性提供了新的见解。
