Changsha Health Vocational College, China.
Reproductive Medicine Center, Department of Obstetrics and Gynecology, The Second Xiangya Hospital, Central South University, China.
J Toxicol Sci. 2024;49(11):467-479. doi: 10.2131/jts.49.467.
Resistance to chemotherapeutic medicines complicates and eventually kills people with ovarian cancer. Nafamostat mesylate (NM) has been used as an adjuvant therapy to enhance chemotherapy sensitivity in several cancers. This study aimed to evaluate the effect of NM on ovarian cancer cells susceptible to carboplatin (CBP) and to determine the underlying mechanism involved. Herein, qRT-PCR, western blot, and IHC were used to analyze mRNA and protein expression. Cell viability and proliferation were measured using the MTT and colony formation assays. Cell migration and invasion were examined using the Transwell assay. Flow cytometry was employed to detect cell apoptosis. The interaction between zinc finger protein 24 (ZNF24) and wingless-type MMTV integration site family member 2b (WNT2B) was validated via the dual-luciferase reporter and Chromatin immunoprecipitation assays. A xenograft nude mouse model was used to assess the effect of NM on CBP sensitivity in vivo. Our results showed that NM intervention inhibited the viability, proliferation, migration, and invasion and facilitated the apoptosis of CBP-resistant ovarian cancer cells. Furthermore, NM sensitized ovarian cancer cells to CBP by upregulating ZNF24. ZNF24 inactivated Wnt/β-catenin signaling by inhibiting the transcription of WNT2B. Additionally, NM enhanced the inhibitory effect of CBP on tumor growth in vivo. Taken together, NM enhanced the CBP sensitivity of ovarian cancer cells by promoting the ZNF24-mediated inactivation of the WNT2B/Wnt/β-catenin axis. These findings suggest a viable treatment approach for improving CBP resistance in ovarian cancer.
耐药性使卵巢癌患者的治疗复杂化并最终导致其死亡。甲磺酸萘莫司他 (NM) 已被用作辅助治疗药物，以提高几种癌症对化疗的敏感性。本研究旨在评估 NM 对顺铂 (CBP) 敏感的卵巢癌细胞的影响，并确定其相关机制。在此，采用 qRT-PCR、western blot 和 IHC 分析 mRNA 和蛋白表达。通过 MTT 和集落形成实验检测细胞活力和增殖。通过 Transwell 检测细胞迁移和侵袭。流式细胞术检测细胞凋亡。通过双荧光素酶报告和染色质免疫沉淀实验验证锌指蛋白 24 (ZNF24) 和无翅型 MMV 整合位点家族成员 2b (WNT2B) 之间的相互作用。使用异种移植裸鼠模型评估 NM 对体内 CBP 敏感性的影响。我们的结果表明，NM 干预抑制了 CBP 耐药性卵巢癌细胞的活力、增殖、迁移和侵袭，并促进了其凋亡。此外，NM 通过上调 ZNF24 使卵巢癌细胞对 CBP 敏感。ZNF24 通过抑制 WNT2B 的转录使 Wnt/β-catenin 信号失活。此外，NM 增强了 CBP 在体内对肿瘤生长的抑制作用。总之，NM 通过促进 ZNF24 介导的 WNT2B/Wnt/β-catenin 轴失活，增强了卵巢癌细胞对 CBP 的敏感性。这些发现为改善卵巢癌对 CBP 的耐药性提供了一种可行的治疗方法。
