Targeting UBE2T Potentiates Gemcitabine Efficacy in Pancreatic Cancer by Regulating Pyrimidine Metabolism and Replication Stress

Xiangyan Jiang; Yong Ma; Tao Wang; Huinian Zhou; Keshen Wang; Wengui Shi; Long Qin; Junhong Guan; Lianshun Li; Bo Long; Jianli Wang; Xiaoying Guan; Huili Ye; Jing Yang; Zeyuan Yu; Zuoyi Jiao

doi:10.1053/j.gastro.2023.02.025

Targeting UBE2T Potentiates Gemcitabine Efficacy in Pancreatic Cancer by Regulating Pyrimidine Metabolism and Replication Stress

Gastroenterology. 2023 Jun;164(7):1232-1247. doi: 10.1053/j.gastro.2023.02.025. Epub 2023 Feb 25.

Authors

Xiangyan Jiang¹, Yong Ma¹, Tao Wang¹, Huinian Zhou¹, Keshen Wang¹, Wengui Shi², Long Qin², Junhong Guan², Lianshun Li¹, Bo Long¹, Jianli Wang³, Xiaoying Guan⁴, Huili Ye², Jing Yang², Zeyuan Yu¹, Zuoyi Jiao⁵

Affiliations

¹ Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu, China.
² Cuiying Biomedical Research Center, Lanzhou University Second Hospital, Lanzhou, Gansu, China.
³ Department of Head and Neck Surgery, Gansu Provincial Cancer Hospital, Lanzhou, Gansu, China.
⁴ Department of Pathology, Lanzhou University Second Hospital, Lanzhou, Gansu, China.
⁵ Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu, China; Cuiying Biomedical Research Center, Lanzhou University Second Hospital, Lanzhou, Gansu, China. Electronic address: jiaozy@lzu.edu.cn.

PMID: 36842710
DOI: 10.1053/j.gastro.2023.02.025

Abstract

Background & aims: Although small patient subsets benefit from current targeted strategies or immunotherapy, gemcitabine remains the first-line drug for pancreatic cancer (PC) treatment. However, gemcitabine resistance is widespread and compromises long-term survival. Here, we identified ubiquitin-conjugating enzyme E2T (UBE2T) as a potential therapeutic target to combat gemcitabine resistance in PC.

Methods: Proteomics and metabolomics were combined to examine the effect of UBE2T on pyrimidine metabolism remodeling. Spontaneous PC mice (LSL-Kras^G12D/+, LSL-Trp53^R172H/+, Pdx1-Cre; KPC) with Ube2t-conditional knockout, organoids, and large-scale clinical samples were used to determine the effect of UBE2T on gemcitabine efficacy. Organoids, patient-derived xenografts (PDX), and KPC mice were used to examine the efficacy of the combination of a UBE2T inhibitor and gemcitabine.

Results: Spontaneous PC mice with Ube2t deletion had a marked survival advantage after gemcitabine treatment, and UBE2T levels were positively correlated with gemcitabine resistance in clinical patients. Mechanistically, UBE2T catalyzes ring finger protein 1 (RING1)-mediated ubiquitination of p53 and relieves the transcriptional repression of ribonucleotide reductase subunits M1 and M2, resulting in unrestrained pyrimidine biosynthesis and alleviation of replication stress. Additionally, high-throughput compound library screening using organoids identified pentagalloylglucose (PGG) as a potent UBE2T inhibitor and gemcitabine sensitizer. The combination of gemcitabine and PGG diminished tumor growth in PDX models and prolonged long-term survival in spontaneous PC mice.

Conclusions: Collectively, UBE2T-mediated p53 degradation confers PC gemcitabine resistance by promoting pyrimidine biosynthesis and alleviating replication stress. This study offers an opportunity to improve PC survival by targeting UBE2T and develop a promising gemcitabine sensitizer in clinical translation setting.

Keywords: Gemcitabine Resistance; Pancreatic Cancer; Pyrimidine Metabolism; Replication Stress; UBE2T.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line, Tumor
Disease Models, Animal
Gemcitabine*
Humans
Mice
Pancreatic Neoplasms* / drug therapy
Pancreatic Neoplasms* / genetics
Pancreatic Neoplasms* / metabolism
Tumor Suppressor Protein p53 / genetics
Ubiquitin-Conjugating Enzymes / genetics
Ubiquitin-Conjugating Enzymes / metabolism

Substances

Gemcitabine
Ubiquitin-Conjugating Enzymes
Tumor Suppressor Protein p53
UBE2T protein, human