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USP5 Binds and Stabilizes EphA2 to Increase Nasopharyngeal Carcinoma Radioresistance
Jie-Yu Tang1,2,3,4, Yun-Xi Peng2,3, Wei Zhu1,4
1Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, China.
Abstract:
Radioresistance poses a major challenge in nasopharyngeal carcinoma (NPC) treatment. However, the underlying mechanism of NPC radioresistance remains poorly understood, and the promising radiosensitizer for NPC radiotherapy is also lacked. Overexpression of USP5 and EphA2 has been linked to various cancers, and both the proteins have attracted considerable attention for the development of new anti-cancer drugs. Here, we report that USP5 interacts with EphA2, and increases EphA2 protein stability and expression by ubiquitin proteasome pathway in the NPC cells. Mebendazole (MBZ), a broad-spectrum anthelmintic drug, transcriptionally inhibits USP5 expression, and then promotes EphA2 ubiquitination degradation in the NPC cells. Functionally, USP5 enhances in vitro and in vivo NPC cell radioresistance via stabilizing EphA2, and MBZ decreases in vitro and in vivo NPC cell radioresistance via targeting USP5/EphA2 axis. Moreover, the levels of USP5 and EphA2 are significantly higher in the radioresistant NPCs than those in the radiosensitive NPCs, and both proteins for predicting patient prognosis are superior to individual protein. These findings suggest that USP5 binds and stabilizes EphA2 by ubiquitin proteasome pathway to promote NPC radioresistance, and MBZ increases NPC radiosensitivity by targeting USP5/EphA2 axis, and is a potential radiosensitizer in NPC and perhaps in other cancers.
Insights
Mebendazole targets the USP5/EphA2 pathway to overcome radioresistance in nasopharyngeal carcinoma (NPC). This study reveals USP5 stabilizes EphA2, promoting cancer cell survival, while Mebendazole reverses this effect, enhancing radiosensitivity.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Nasopharyngeal carcinoma (NPC) exhibits significant radioresistance, hindering effective radiotherapy.
- The molecular mechanisms driving NPC radioresistance are not fully understood, and effective radiosensitizers are needed.
- USP5 and EphA2 overexpression is implicated in various cancers, making them potential therapeutic targets.
Purpose of the Study:
- To elucidate the role of USP5 and EphA2 in NPC radioresistance.
- To investigate the mechanism by which USP5 affects EphA2 stability and expression.
- To evaluate Mebendazole (MBZ) as a potential radiosensitizer by targeting the USP5/EphA2 axis in NPC.
Main Methods:
- Investigated the interaction between USP5 and EphA2 in NPC cells using molecular biology techniques.
- Assessed the effect of USP5 on EphA2 protein stability and expression via the ubiquitin-proteasome pathway.
- Examined the impact of Mebendazole (MBZ) on USP5 expression, EphA2 ubiquitination, and NPC cell radiosensitivity in vitro and in vivo.
- Correlated USP5 and EphA2 expression levels with NPC radiosensitivity and patient prognosis.
Main Results:
- USP5 interacts with EphA2, enhancing its stability and expression through the ubiquitin-proteasome pathway in NPC cells.
- Mebendazole (MBZ) inhibits USP5 expression, leading to increased EphA2 ubiquitination and degradation, thereby reducing NPC cell radioresistance.
- USP5 promotes both in vitro and in vivo NPC radioresistance by stabilizing EphA2.
- MBZ decreases NPC radioresistance by targeting the USP5/EphA2 axis.
- Higher levels of USP5 and EphA2 are observed in radioresistant NPC tissues compared to radiosensitive ones.
- Combined detection of USP5 and EphA2 offers superior prognostic prediction for NPC patients compared to individual markers.
Conclusions:
- USP5 stabilizes EphA2 via the ubiquitin-proteasome pathway, contributing to NPC radioresistance.
- Mebendazole (MBZ) enhances NPC radiosensitivity by targeting the USP5/EphA2 axis.
- USP5 and EphA2 serve as potential biomarkers for predicting NPC prognosis and radioresistance.
- MBZ demonstrates potential as a radiosensitizer for NPC radiotherapy and possibly other cancers.
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