The role of IGF2BP3/SPOP/c-Myc loop in paclitaxel resistance of endometrial cancer
Paclitaxel combination therapy is the main chemotherapy regimen for endometrial cancer (EC); however, subsequent drug resistance is a bottleneck limiting its widespread clinical application. We found that human insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) was abnormally elevated in paclitaxel-resistant EC cells and confirmed that the reduction of IGF2BP3 can effectively improve the sensitivity of EC cells to paclitaxel in vitro and in vivo. Mechanistically, elevated IGF2BP3 promotes the half-life of c-Myc by competitively inhibiting Speckle-type POZ protein (SPOP)-mediated ubiquitination and degradation of c-Myc. As a transcription factor, c-Myc can bind to the promoter of IGF2BP3, thus contributing to the increased transcription of IGF2BP3 via positive feedback and forming a signaling loop that ultimately causes the accumulation of c-Myc-induced paclitaxel resistance. Based on these findings, the application of c-Myc inhibitors (10058-F4) combined with paclitaxel helped paclitaxel-resistant EC cells regain paclitaxel sensitivity in vitro and in vivo. Together, we reveal the underlying mechanism of paclitaxel resistance in endometrial cancer cells and provide insights into treatment strategies for paclitaxel-resistant EC patients.
Authors
- Gun Chen
- Xiaofeng Jin (ORCID: https://orcid.org/0000-0003-0801-8638)
- Mengxiang Zhao (ORCID: https://orcid.org/0000-0002-9823-0917)
- Fengguang Zhai
- Yuxuan Li (ORCID: https://orcid.org/0000-0001-9904-2961)
- Ziqing Zhan
- J. L. Shi (ORCID: https://orcid.org/0009-0001-4575-3108)
- Yuxuan Wang (ORCID: https://orcid.org/0000-0001-9117-0619)
- Yidong Ge (ORCID: https://orcid.org/0000-0003-0964-0293)
- Haoyun Wang (ORCID: https://orcid.org/0000-0002-2972-2627)
- Shuyan Wang (ORCID: https://orcid.org/0000-0003-0380-5798)
- Meng Ye (ORCID: https://orcid.org/0000-0001-5827-3704)
- Mao Jun (ORCID: https://orcid.org/0000-0003-3959-2309)
- Jianan Zhao (ORCID: https://orcid.org/0000-0003-4105-1683)
- Lei Hu (ORCID: https://orcid.org/0000-0002-5338-0903)
- Siyuan Wang (ORCID: https://orcid.org/0000-0001-6550-4064)
- Zongdong Yu
- Pengrong Lou
- Lianbao Kong (ORCID: https://orcid.org/0000-0001-7209-0365)
Institutions
- Shangrao Normal University (CN)
- Ningbo University (CN)
- University of Nottingham Ningbo China (CN)
- Ningbo Medical Center Lihuili Hospital (CN)
- Ningbo University Affiliated Hospital (CN)
- Ningbo First Hospital (CN)
Publication Details
- Journal
- Communications Biology
- Published
- 2025-04-17
- DOI
- https://doi.org/10.1038/s42003-025-08065-0
- Citations
- 3
- Primary Topic
- Endometrial and Cervical Cancer Treatments
- Type
- article
- Field-Weighted Citation Impact
- 6.17
Funders
- National Natural Science Foundation of China
- Ningbo University
- Natural Science Foundation of Ningbo