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Synergistic antitumor efficacy of gemcitabine and cisplatin to induce ferroptosis in pancreatic ductal adenocarcinoma via Sp1-SAT1-polyamine metabolism pathway

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Abstract

Purpose

The combination of cisplatin and gemcitabine-based chemotherapy has been recommended as a preferred regimen for pancreatic ductal adenocarcinoma (PDAC) patients with germline-based mutations. However, the underlying mechanism remains poorly elucidated. Therefore, our study aimed to explore the mechanistic basis of the cell-killing activity of gemcitabine plus cisplatin and identify potential therapeutic targets.

Methods

First, we explored the synergistic cytotoxic effects of gemcitabine and cisplatin on PDAC through in vitro and in vivo experiments. Then, we investigated ferroptosis-related biomarkers, to assess the impact of the combination therapy on ferroptosis. Using bioinformatics methods, we identified SAT1 as a potential key mediator of ferroptosis induced by gemcitabine and cisplatin. We tested the polyamine levels in PDAC cells by LC–MS after overexpressed or knocked down SAT1, and explored the role of polyamines in ferroptosis using exogenous supplementation. Finally, we explored the regulatory effect of Sp1 on SAT1 through ChIP-qPCR and dual-luciferase reporter assay.

Results

Gemcitabine plus cisplatin enhanced cell death and induced ferroptosis in PDAC. This combination upregulated SAT1 transcription by inhibiting Sp1. SAT1 activation promoted the catabolism of spermine and spermidine, leading to iron accumulation and lipid peroxide generation, ultimately resulting in ferroptosis.

Conclusions

In summary, our findings suggested the gemcitabine and cisplatin combination therapy induced ferroptosis in a GSH-independent manner in PDAC. The combined treatment inhibited Sp1 and upregulated SAT1 transcription, leading to the breakdown of spermine and spermidine. Therefore, targeting SAT1-induced polyamine metabolism may represent a promising therapeutic strategy for PDAC.

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Data availability

The original contributions presented in the study are included in the article/Supplementary Material, and the RNA sequencing data were accessed from GEO database (https://www.ncbi.nlm.nih.gov/geo/), further inquiries can be directed to the corresponding authors.

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Funding

This research was funded by the National Natural Science Foundation of China (Grant No. 81870390), Scientific Research Project of Wuhan Science and Technology Bureau (No: 2019020701011476), and Hubei Provincial Natural Science and Technology Fund (No:2023AFB458).

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Author notes

  1. Wanhui Wei and Yuanyuan Lu have contributed equally to this work.

Authors and Affiliations

  1. Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China

    Wanhui Wei, Jinwen Yin, Youwei Wang, Qiu Zhao & Lan Liu

  2. Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China

    Wanhui Wei, Jinwen Yin, Youwei Wang, Qiu Zhao & Lan Liu

  3. Department of Gastroenterology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Wanhui Wei & Heng Zhang

  4. Key Laboratory for Molecular Diagnosis of Hubei Province, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Wanhui Wei & Heng Zhang

  5. Department of Gastroenterology, Wuhan Third Hospital, Tongren Hospital of Wuhan University, Wuhan, China

    Yuanyuan Lu

  6. Department of Hematology, West China Hospital, Sichuan University, Chengdu, China

    Qian Hu

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  1. Wanhui Wei
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Contributions

Conceptualization, WW, QH, QZ, and LL; methodology, WW, YL, and QH; software, JY, and QH; validation, WW, WY, and YL; formal analysis, YL; investigation, JY; data curation, WW, and YL; writing—original draft preparation, WW; writing—review and editing, WW and LL; visualization, WW; supervision, HZ, QZ, and LL. All authors have read and agreed to the published version of the manuscript.

Corresponding authors

Correspondence to Heng Zhang, Qiu Zhao or Lan Liu.

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The animal study (ZN2021191) was reviewed and approved by the Zhongnan Hospital of Wuhan University Institutional Animal Care Animal Welfare Committee.

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Supplementary Information

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13402_2023_870_MOESM1_ESM.tif

Supplementary file1 S-Fig 1. Establishment of the stable PANC-1 cell line with knockdown of SAT1. A. Transfection efficiency of shSAT1 lentiviral vector was observed by fluorescence microscope in PANC-1cells. B. Western blot assay for SAT1 in the stable PANC-1 cell line with knockdown of SAT1 in the presence or absence combination treatment of gemcitabine and cisplatin. (TIF 40751 KB)

13402_2023_870_MOESM2_ESM.tif

Supplementary file2 S-Fig 2. Repetitive Western blot bands and grayscale analysis in PDAC cells treated with mono or combination of gemcitabine and cisplatin. (TIF 32396 KB)

Supplementary file3 S-Fig 3. The mRNA of other candidate genes treated with gemcitabine and cisplatin. (TIF 27383 KB)

13402_2023_870_MOESM4_ESM.tif

Supplementary file4 S-Fig 4. Repetitive Western blot bands and grayscale analysis in PDAC cells transfected with SAT1 overexpression plasmid. (TIF 29400 KB)

13402_2023_870_MOESM5_ESM.tif

Supplementary file5 S-Fig5. Repetitive Western blot bands and grayscale analysis in PDAC cells transinfected with SAT1 shRNA. (TIF 31632 KB)

13402_2023_870_MOESM6_ESM.tif

Supplementary file6 S-Fig6. Repetitive Western blot bands and grayscale analysis in PDAC cells supplemented with spermidine or spermine. (TIF 31290 KB)

13402_2023_870_MOESM7_ESM.tif

Supplementary file7 S-Fig7. Repetitive Western blot bands and grayscale analysis in PDAC cells transfected with siSp1. (TIF 27157 KB)

13402_2023_870_MOESM8_ESM.tif

Supplementary file8 S-Fig 8. Sp1 did not bind to the predicted binding site 1 of SAT1 promoter in PDAC. A-B. ASPC-1 and PANC-1 cells were collected for ChIP-PCR (A.) and ChIP-qPCR (B.) with anti-Sp1 antibody and specific primers for binding site 1. IgG was used as negative control. (TIF 26823 KB)

13402_2023_870_MOESM9_ESM.tif

Supplementary file9 S-Fig 9. Sp1 inhibited SAT1 not via the Sp1-HDAC1 complex in PDAC. A. Binding affinity between Sp1 and HDAC1 in PDAC cells, as detected with Co-IP assay (TIF 28621 KB)

Supplementary file10 (XLSX 12 KB)

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Wei, W., Lu, Y., Hu, Q. et al. Synergistic antitumor efficacy of gemcitabine and cisplatin to induce ferroptosis in pancreatic ductal adenocarcinoma via Sp1-SAT1-polyamine metabolism pathway. Cell Oncol. 47, 321–341 (2024). https://doi.org/10.1007/s13402-023-00870-1

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