NEK6 dampens FOXO3 nuclear translocation to stabilize C-MYC and promotes subsequent de novo purine synthesis to support ovarian cancer chemoresistance

• Published in: Cell death & disease 2024-09, Vol.15 (9), p.661-17, Article 661
• Main Authors: Liu, Jingchun, Wang, Haoyu, Wan, Huanzhi, Yang, Jiang, Gao, Likun, Wang, Zhi, Zhang, Xiaoyi, Han, Wuyue, Peng, Jiaxin, Yang, Lian, Hong, Li
• Format: Article
• Language: English
• Subjects: 101/58; 13/2; 13/31; 13/51; 14/19; 38; 42; 45; 631/67/1517/1709; 631/67/2327; 631/80/389/2023/2022; 82/1; 82/29; 82/83; 96; 96/2; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; c-Myc protein; Cdc4 protein; Cell Biology; Cell Culture; Cell growth; Cell Line, Tumor; Cell Nucleus - metabolism; Cell Proliferation - drug effects; Cell survival; Chemoresistance; DNA damage; DNA repair; Drug Resistance, Neoplasm - drug effects; F-Box-WD Repeat-Containing Protein 7 - genetics; F-Box-WD Repeat-Containing Protein 7 - metabolism; Female; Forkhead Box Protein O3 - genetics; Forkhead Box Protein O3 - metabolism; FOXO3 protein; Gene Expression Regulation, Neoplastic - drug effects; Humans; Immunology; Life Sciences; Mass spectroscopy; Metabolic pathways; Metabolism; Metabolomics; Mice; Mice, Nude; Myc protein; NIMA-Related Kinases - genetics; NIMA-Related Kinases - metabolism; Nuclear transport; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Phosphorylation; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Purines; Purines - metabolism; Purines - pharmacology; Tumors; Ubiquitination
• ISSN: 2041-4889; 2041-4889
• 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.