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

Sep 21, 2026

Uploaded by Theodore

De novo purine synthesis supports tumor cell survival, yet its specific role in ovarian cancer chemoresistance remains unclear. This study analyzes metabolic differences between chemosensitive and chemoresistant ovarian cancer tissues using mass spectrometry-based metabolomics, and evaluates cell growth, metabolism, chemoresistance, and DNA damage repair in vitro. Tumor growth and chemoresistance are further assessed in vivo using ovarian cancer xenografts. The work identifies higher purine abundance and NEK6 expression in chemoresistant cancers, showing that NEK6 inhibition reduces de novo purine synthesis and diminishes chemoresistance via a FOXO3 - FBXW7 - C-MYC axis, with paeonol enhancing chemosensitivity.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages17

Reading Time43 min

AccessFree to download

Introduction

Purine metabolism and tumor progression

Ovarian cancer chemoresistance and metabolic pathways

NEK6 in cancer therapy resistance

Materials and Methods

Cell culture

[www.nature.com/cddis](www.nature.com/cddis) ARTICLE OPEN NEK6 dampens FOXO3 nuclear translocation to stabilize C-MYCand promotes subsequent de novo purine synthesis to support ovarian cancer chemoresistance Jingchun Liu1,2, Haoyu Wang1,2, Huanzhi Wan2, Jiang Yang 3, Likun Gao4, Zhi Wang 1,2, Xiaoyi Zhang2, Wuyue Han1,2, Jiaxin Peng1,2, Lian Yang1,2 and Li Hong 1 ✉ © The Author(s) 2024 | | | | | --- | --- | --- | | | 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. | | | | | | | | | | | | Cell Death and Disease (2024)15:661; [https://doi.org/10.1038/s41419-024-07045-2](https://doi.org/10.1038/s41419-024-07045-2) | | | | | | INTRODUCTION Purine metabolism stands as a pivotal branch within nucleotide metabolism, playing a crucial role in maintaining the homeostasis of DNA and RNA, essential for normal cell growth. Furthermore, purines contribute to immunomodulation and energy metabolism, and potentially serve as vital cofactors in biochemical reactions [1] . Disruptions in purine metabolism can trigger uncontrolled cell growth and disrupt normal cellular processes, impacting proliferation, migration, and cell death. De novo purine synthesis is frequently heightened in tumor cells, fostering accelerated proliferation and the acquisition of malignant properties. Ovarian cancer stands as an extremely perilous malignant gynecologic neoplasm, impacting women globally and imposing a substantial social burden. Statistically, ovarian cancer ranks as the ﬁfth leading cause of cancer-related deaths among women worldwide, with a relative 5-year survival rate of 49%[2, 3] . The profoundly malignant and chemoresistant nature of ovarian cancer presents a formidable global challenge. Previous studies have indicated that abnormalities in several metabolic pathways, including glucose metabolism, lipid metabolism, iron metabolism, and amino acid metabolism, are associated with chemoresistance in ovarian cancer [4–8] . However, the correlation between de novo purine synthesis and chemoresistance in ovarian cancer remains to be elucidated. NEK6, a member of the NIMA-related kinase family, is widely distributed in human tissues and intricately linked to cell mitosis

FAQs

What role does de novo purine synthesis play in ovarian cancer chemoresistance?

The study links enhanced de novo purine synthesis with chemoresistant ovarian cancer, suggesting it helps tumor cells survive after chemotherapy by supporting repair processes and sustaining growth-related metabolism.

How does NEK6 regulate FOXO3 to influence C-MYC and purine synthesis?

NEK6 directly interacts with FOXO3 and promotes phosphorylation at S7, which inhibits FOXO3 nuclear translocation. This reduces FOXO3-driven FBXW7 transcription, suppressing C-MYC ubiquitination and degradation, thereby supporting de novo purine synthesis.

How does inhibiting NEK6 or using paeonol affect chemosensitivity?

Inhibiting NEK6 decreases de novo purine synthesis and weakens chemoresistance in ovarian cancer cells. Paeonol, by inhibiting NEK6-mediated purine metabolism, further suppresses de novo purine synthesis and enhances chemosensitivity.

Sep 21, 2026

Uploaded by Theodore