Department of Gynecology and Obstetrics, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
The First Clinical School of Wuhan University, Wuhan University, Wuhan, Hubei, China.
Cell Death Dis. 2024 Sep 10;15(9):661. doi: 10.1038/s41419-024-07045-2.
De novo purine synthesis metabolism plays a crucial role in tumor cell survival and malignant progression. However, the specific impact of this metabolic pathway on chemoresistance in ovarian cancer remains unclear. This study aims to elucidate the influence of de novo purine synthesis on chemoresistance in ovarian cancer and its underlying regulatory mechanisms. We analyzed metabolic differences between chemosensitive and chemoresistant ovarian cancer tissues using mass spectrometry-based metabolomics. Cell growth, metabolism, chemoresistance, and DNA damage repair characteristics were assessed in vitro using cell line models. Tumor growth and chemoresistance were assessed in vivo using ovarian cancer xenograft tumors. Intervention of purines and NEK6-mediated purine metabolism on chemoresistance was investigated at multiple levels. Chemoresistant ovarian cancers exhibited higher purine abundance and NEK6 expression. Inhibiting NEK6 led to decreased de novo purine synthesis, resulting in diminished chemoresistance in ovarian cancer cells. Mechanistically, NEK6 directly interacted with FOXO3, contributing to the phosphorylation of FOXO3 at S7 through its kinase activity, thereby inhibiting its nuclear translocation. Nuclear FOXO3 promoted FBXW7 transcription, leading to c-MYC ubiquitination and suppression of de novo purine synthesis. Paeonol, by inhibiting NEK6, suppressed de novo purine synthesis and enhanced chemosensitivity. The NEK6-mediated reprogramming of de novo purine synthesis emerges as a critical pathway influencing chemoresistance in ovarian cancer. Paeonol exhibits the potential to interfere with NEK6, thereby inhibiting chemoresistance.
从头合成嘌呤代谢在肿瘤细胞存活和恶性进展中起着至关重要的作用。然而，该代谢途径对卵巢癌化疗耐药性的具体影响尚不清楚。本研究旨在阐明从头合成嘌呤代谢对卵巢癌化疗耐药性的影响及其潜在的调控机制。我们使用基于质谱的代谢组学分析方法分析了化疗敏感和耐药卵巢癌组织之间的代谢差异。我们使用细胞系模型在体外评估了细胞生长、代谢、化疗耐药性和 DNA 损伤修复特征。我们使用卵巢癌异种移植瘤在体内评估了肿瘤生长和化疗耐药性。我们在多个层面研究了嘌呤和 NEK6 介导的嘌呤代谢对化疗耐药性的干预作用。耐药性卵巢癌表现出更高的嘌呤丰度和 NEK6 表达。抑制 NEK6 导致从头合成嘌呤减少，从而降低卵巢癌细胞的化疗耐药性。机制上，NEK6 直接与 FOXO3 相互作用，通过其激酶活性将 FOXO3 磷酸化在 S7 位，从而抑制其核转位。核 FOXO3 促进 FBXW7 转录，导致 c-MYC 泛素化并抑制从头合成嘌呤。丹皮酚通过抑制 NEK6 抑制从头合成嘌呤并增强化疗敏感性。NEK6 介导的从头合成嘌呤的重编程是影响卵巢癌化疗耐药性的关键途径。丹皮酚具有干扰 NEK6 的潜力，从而抑制化疗耐药性。
