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Uricase sensitizes hepatocellular carcinoma cells to 5-fluorouracil through uricase-uric acid-UMP synthase axis

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Abstract

Conventional chemotherapy plays a key role in hepatocellular carcinoma (HCC) treatment, however, with intrinsic or acquired chemoresistance being a major constraint. Here, we aimed to identify potential target to reverse such chemoresistance. In the present study, we found significant difference in uridine monophosphate synthetase (UMPS) expression between 5-FU resistant and sensitive HCC cell lines and the overexpression or downregulation of UMPS impacted 5-FU response in HCC cells. We further found that inhibition of UMPS activity with uric acid at concentration present in human plasma decreased the 5-FU sensitivity of HCC cells, while reduction of uric acid levels with uricase improved the 5-FU sensitivity of HCC cells as well as colorectal cancer cells. In vivo studies also suggested that modulation of uric acid levels did affect 5-FU sensitivity of tumors. These data indicated that UMPS was correlated with the 5-FU resistance in HCC cells and uricase sensitized cancer cells to 5-FU through uricase-uric acid-UMP synthase axis, which provided a potential strategy to improve the efficacy of 5-FU-based chemotherapy for human cancers.

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All data generated or analyzed during this study are included in this published article.

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Funding

This study was supported by the National Natural Science Foundation of China (No.81773626), Natural Science Foundation of Zhejiang Province (No.LQ21H31006), Medical and Health Science and Technology Project of Zhejiang Province (No.2020KY104), and Science and Technology project of Zhejiang Academy of Medical Sciences (No.2019D001).

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Author notes

  1. Saihong Yu and Zhuduo Li contributed equally to this work.

Authors and Affiliations

  1. School of Bioengineering, Hangzhou Medical College, Zhejiang Province, Hangzhou, 310013, China

    Saihong Yu, Zhuduo Li, Linglan Tu, Yiyi Pu, Dongmei Yan, Xiaoju Wang, Xiaoliang Zheng & Jie Yu

  2. Zhejiang Provincial Key Laboratory of Neuropsychiatric Drug Research, Hangzhou Medical College, Zhejiang Province, Hangzhou, 310013, China

    Saihong Yu & Jie Yu

Authors
  1. Saihong Yu
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  5. Dongmei Yan
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  8. Jie Yu
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Contributions

JY and XLZ conceived and supervised the study; experiments were primarily performed by SHY and ZDL with contribution from LLT, YYP, and DMY. All authors read, reviewed, edited, and approved the manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

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Correspondence to Xiaoliang Zheng or Jie Yu.

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Key Points

UMPS was correlated with the 5-FU resistance in HCC cells.

Inhibition of UMPS activity with uric acid reduced the 5-FU sensitivity of HCC cells.

Uricase sensitized HCC cells to 5-FU through uricase-uric acid-UMP Synthase axis.

Modulation of uric acid levels provided a novel strategy to improve the efficacy of 5-FU-based chemotherapy.

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Yu, S., Li, Z., Tu, L. et al. Uricase sensitizes hepatocellular carcinoma cells to 5-fluorouracil through uricase-uric acid-UMP synthase axis. J Physiol Biochem 78, 679–687 (2022). https://doi.org/10.1007/s13105-022-00894-5

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  • DOI: https://doi.org/10.1007/s13105-022-00894-5

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