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SLC35F2–SYVN1–TRIM59 axis critically regulates ferroptosis of pancreatic cancer cells by inhibiting endogenous p53

Oncogene volume 42, pages 3260–3273 (2023)Cite this article

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Abstract

Pancreatic cancer cells undergo intricate metabolic reprogramming to sustain their survival and proliferation. p53 exhibits a dual role in tumor cell ferroptosis. However, the precise role and mechanisms underlying wild-type p53 activation in promoting ferroptosis in pancreatic cancer cells remain obscure. In this study, we applied bioinformatics tools and performed an analysis of clinical tissue sample databases and observed a significantly upregulated expression of solute carrier family 35 member F2 (SLC35F2) in pancreatic cancer tissues. Our clinical investigations indicated that elevated SLC35F expression was related to adverse survival outcomes. Through multi-omics analyses, we discerned that SLC35F2 influences the transcriptome and inhibits ferroptosis in pancreatic cancer cells. Moreover, our findings reveal the pivotal involvement of p53 in mediating SLC35F2-mediated ferroptosis, both in vitro and in vivo. SLC35F2 inhibits ferroptosis by facilitating TRIM59-mediated p53 degradation. Further mechanistic investigations demonstrated that SLC35F2 competitively interacts with the E3 ubiquitin ligase SYVN1 of TRIM59, thereby stabilizing TRIM59 expression and consequentially promoting p53 degradation. Utilizing protein 3D structure analysis and drug screening, we identified irinotecan hydrochloride and lapatinib ditosylate as compounds targeting SLC35F2, augmenting the antitumor effect of imidazole ketone erastin (IKE) in a wild-type p53 patient-derived xenograft (PDX) model. However, in the p53 mutant PDX model, irinotecan hydrochloride and lapatinib ditosylate did not alter the sensitivity of the tumor xenograft model to IKE-triggered ferroptosis. In summary, our work establishes a novel mechanism wherein the SLC35F2–SYVN1–TRIM59 axis critically regulates ferroptosis of pancreatic cancer cells by inhibiting endogenous p53. Thus, SLC35F2 emerges as a promising therapeutic target for treating pancreatic cancer.

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Fig. 1: SLC35F2 expression is upregulated, correlating with the progression and prognosis of patients with pancreatic adenocarcinoma (PAAD).
Fig. 2: SLC35F2 exerts transcriptomic effect on ferroptosis in pancreatic cancer (PC) cells.
Fig. 3: SLC35F2 regulates the p53 signaling pathway to inhibit ferroptosis in pancreatic cancer (PC) cells.
Fig. 4: p53 is essential for SLC35F2-mediated ferroptosis in pancreatic cancer (PC) cells.
Fig. 5: SLC35F2 promotes p53 degradation mediated by the ubiquitin proteasome.
Fig. 6: SLC35F2 inhibits ferroptosis in pancreatic cancer cells depending on TRIM59-mediated p53 degradation.
Fig. 7: SLC35F2 competitively binds to SYVN1 to increase TRIM59 expression.
Fig. 8: Targeting SLC35F2 enhances the anticancer activity of imidazole ketone erastin (IKE).

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Data availability

All data in our study are available from the corresponding author upon reasonable request.

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Funding

This work was supported by grants from the National Natural Science Foundation of China (82203493,82372769, 82060454, 81960522, 82160364, 82060449, and 82060466), the Project of the Jiangxi Provincial Department of Science and Technolog (20212ACB206024, 20212BCJ23022, 20232BCJ22016, 20224BAB206081, 20202BABL206084, 20192BAB205068, 20212BAB206044, and 20202BAB216032). The key research and development program of Jiangxi Province of China (20203BBGL73143). Outstanding Youth Fund of Jiangxi Cancer Hospital (2021DYS06).

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Author notes

  1. These authors contributed equally: Ben Che, Yunyan Du, Rongfa Yuan, Han Xiao.

Authors and Affiliations

  1. Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330000, China

    Ben Che, Rongfa Yuan, Han Xiao, Wenming Zhang, Jun Shao, Hongcheng Lu, Kai Wang & Leifeng Chen

  2. Department of Pharmacology, School of Pharmaceutical Science, Nanchang University, Nanchang, 330000, China

    Yunyan Du

  3. Department of Urology Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330000, China

    Yi Yu & Mingfeng Xiang

  4. Department of Orthopedics, The Second Affiliated Hospital of Nanchang University, Nanchang, 330000, China

    Liang Hao

  5. Department of General Surgery, The Affiliated Children’s Hospital of Nanchang University, Nanchang, 330000, China

    Shouhua Zhang

  6. Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330000, China

    Xiaohong Du

  7. Jiangxi Province Key Laboratory of Molecular Medicine, Second Affiliated Hospital of Nanchang University, Nanchang, 330000, China

    Xiuxia Liu & Kai Wang

  8. Department of Abdominal Surgery, Jiangxi Cancer Hospital, Nanchang, 330029, China

    Wei Zhou

  9. Cancer Center, Renmin Hospital of Wuhan University, Wuhan, 430060, China

    Leifeng Chen

  10. Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, 330000, China

    Leifeng Chen

  11. Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330000, China

    Leifeng Chen

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Contributions

FLC conceived the research concept and design. FLC, KW, MW, WZ, and XXL implemented the methodological development and drafted, reviewed, and revised the manuscript. BC, YYD, FRY, HX, JS, SHZ, and QF collected, analyzed, and interpretated the data and conducted statistical analysis of the data; MFX, YY, LH, and XHD extended material and technical support. All the authors read and authorized the final version of the paper.

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Correspondence to Xiuxia Liu, Wei Zhou, Kai Wang or Leifeng Chen.

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Che, B., Du, Y., Yuan, R. et al. SLC35F2–SYVN1–TRIM59 axis critically regulates ferroptosis of pancreatic cancer cells by inhibiting endogenous p53. Oncogene 42, 3260–3273 (2023). https://doi.org/10.1038/s41388-023-02843-y

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