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Profiling Ubiquitin and Ubiquitin-like Dependent Post-translational Modifications and Identification of Significant Alterations
Published on: November 7, 2019
UDP-glucose 6-dehydrogenase lessens sorafenib sensitivity via modulating unfolded protein response
Bao Guo1, Xiaoyan Xu2, Miaomiao Shao3
1NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
Abstract:
As the first-generation targeted therapy, sorafenib remains an effective single-drug treatment for advanced hepatocellular carcinoma (HCC). Unfortunately, the existence of resistance restricts the long-term benefit of patients. UDP-glucose 6-dehydrogenase (UGDH) is the key enzyme of glucuronic acid metabolism which was largely reported in mediating drug systemic elimination. In this study, we explore its critical role in regulating sorafenib sensitivity. Here we find sorafenib exposure could activate glucuronic acid metabolism, accompanied with the elevated expression of UGDH. Interference with the route by silencing UGDH could boost HCC cells sensitivity to sorafenib. Meanwhile, the analysis of HCC patients with sorafenib treatment displayed that low UGDH expression predicted superior prognosis. Further screening assay suggested that unfolded protein response (UPR) involves in UGDH silencing-mediated apoptosis. Xenograft model confirmed that combined UGDH intervention could significantly improve sorafenib efficacy. Our results reveal the impact of sorafenib exposure on glucuronic acid metabolism reprogramming and provide UGDH as a promising target to improve sorafenib efficacy.
Insights
Sorafenib resistance in liver cancer (HCC) can be overcome by targeting UDP-glucose 6-dehydrogenase (UGDH). Silencing UGDH enhances sorafenib sensitivity and improves patient prognosis, offering a new therapeutic strategy.
Area of Science:
- Biochemistry
- Oncology
- Molecular Biology
Background:
- Sorafenib is a first-generation targeted therapy for advanced hepatocellular carcinoma (HCC).
- Drug resistance limits the long-term efficacy of sorafenib in HCC patients.
- UDP-glucose 6-dehydrogenase (UGDH) is crucial in glucuronic acid metabolism and drug elimination.
Purpose of the Study:
- To investigate the role of UGDH in regulating sorafenib sensitivity in HCC.
- To explore UGDH as a potential therapeutic target for overcoming sorafenib resistance.
Main Methods:
- Sorafenib exposure and UGDH expression analysis in HCC cells.
- UGDH gene silencing experiments.
- Analysis of HCC patient data treated with sorafenib.
- Unfolded protein response (UPR) screening.
- Xenograft model studies.
Main Results:
- Sorafenib treatment activates glucuronic acid metabolism and increases UGDH expression.
- Silencing UGDH enhances HCC cell sensitivity to sorafenib.
- Low UGDH expression in HCC patients correlates with better sorafenib treatment outcomes.
- UGDH silencing-induced apoptosis involves the unfolded protein response (UPR).
- Combined UGDH intervention and sorafenib significantly improve efficacy in xenograft models.
Conclusions:
- Sorafenib exposure reprograms glucuronic acid metabolism via UGDH.
- UGDH is a promising therapeutic target to enhance sorafenib efficacy in HCC.
- Targeting UGDH represents a novel strategy to overcome sorafenib resistance in liver cancer.
