| Title: |
Targeting Mevalonate Pathway Enhances the efficacy of 5-Fluorouracil by regulating pyroptosis |
| Authors: |
Xing, Zongrui; Ma, Yong; Jiang, Xiangyan; Qing, Huiguo; Wu, Yuxia; Che, Shengfu; Gao, Zhongti; Wang, Keshen; Wang, Tao; He, Qichen; Li, Zhigang; Zhao, Bin; Liu, Wenbo; Sun, Haonan; Yu, Zeyuan |
| Publisher Information: |
Springer Science and Business Media LLC |
| Publication Year: |
2024 |
| Description: |
The 5-fluorouracil (5-FU)-based chemotherapy regimen is a primary strategy for treating pancreatic cancer (PC).However, challenges related to 5-FU resistance persist. Investigating the mechanisms of 5-FU resistance and identifying a clinically viable therapeutic strategy are crucial for improving the prognosis of PC. Here, through clinical samples analysis, we found that the expression of 3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR),the rate-limiting enzyme in mevalonate metabolism, is negatively correlated with the efficacy of 5-FU treatment. There is a significant correlation between HMGCR and the pyroptosis marker Gasdermin D (GSDMD),and the HMGCR inhibitor simvastatin can significantly inhibit the activation of pyroptosis signaling. The exogenous addition of geranylgeranyl pyrophosphate (GGPP),a key metabolite of the mevalonate pathway, can significantly reduce sensitivity to 5-FU,and simvastatin combined with 5-FU demonstrates a strong synergistic effect. Furthermore, in organoid models and genetically engineered mice with spontaneous PC, the combination of simvastatin and 5-FU significantly inhibits tumor growth. In conclusion, our study reveals the critical role of the mevalonate pathway in 5-FU resistance and proposes a clinically feasible combination therapy strategy. |
| Document Type: |
other/unknown material |
| Language: |
unknown |
| DOI: |
10.21203/rs.3.rs-5024083/v2 |
| Availability: |
http://dx.doi.org/10.21203/rs.3.rs-5024083/v2; https://www.researchsquare.com/article/rs-5024083/v2; https://www.researchsquare.com/article/rs-5024083/v2.html |
| Rights: |
https://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.76A7F6AB |
| Database: |
BASE |