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

Authors :
Jingchun Liu
Haoyu Wang
Huanzhi Wan
Jiang Yang
Likun Gao
Zhi Wang
Xiaoyi Zhang
Wuyue Han
Jiaxin Peng
Lian Yang
Li Hong
Source :
Cell Death and Disease, Vol 15, Iss 9, Pp 1-17 (2024)
Publication Year :
2024
Publisher :
Nature Publishing Group, 2024.

Abstract

Abstract 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.

Subjects

Subjects :
Cytology
QH573-671

Details

Language :
English
ISSN :
20414889
Volume :
15
Issue :
9
Database :
Directory of Open Access Journals
Journal :
Cell Death and Disease
Publication Type :
Academic Journal
Accession number :
edsdoj.109248229e2c45ebaa72a348692c7c54
Document Type :
article
Full Text :
https://doi.org/10.1038/s41419-024-07045-2