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PinX1 inhibits migrasomes-mediated mitochondrial transfer to confer cisplatin sensitivity in nasopharyngeal carcinoma

Oncogene (2026)Cite this article

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Abstract

Chemotherapy resistance is a major factor contributing to the failure of nasopharyngeal carcinoma (NPC) treatment. Migrasomes can export damaged mitochondria out of the cell, and the timely removal of damaged mitochondria is key to cancer cell resistance. However, whether migrasomes regulate tumor resistance remains unknown. Here, we elucidated the role and mechanism of migrasomes in chemoresistance of NPC. We found that the formation of migrasomes was increased in cisplatin-resistant NPC cells, and inhibiting migrasome formation reduced cisplatin resistance. PinX1 was lowly expressed in tumor tissues of patients with high migrasome scores. Upstream mechanism analyses showed that TP53 was effectively bound to the promoter of PinX1, thereby enhancing its transcriptional activity. Knockdown of PinX1 facilitated migrasome formation via its telomerase inhibitory domain 252–328aa region binding to Rab11a, which relied on serine residues at the N-terminal 25aa site for promoting migrasome formation. Mechanistically, PinX1 recruited RanBP2 to induce the SUMOylation of Rab11a, leading to the degradation of Rab11a at the K207 site. Furthermore, PinX1 reduced cancer cell energy metabolism by inhibiting the export of damaged mitochondria via migrasomes. Collectively, TP53-activated PinX1 recruits RanBP2 to Rab11a, triggering Rab11a K207 SUMOylation and degradation, leading to impaired migrasome formation and mitochondrial transfer, and ultimately suppresses cisplatin resistance in NPC. Our study provides a new target for clinical reversal of chemotherapy resistance in patients with NPC.

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Fig. 1: Migrasomes are increased in cisplatin (DDP)-resistant nasopharyngeal carcinoma (NPC) cells, and migrasomes promote DDP resistance.
The alternative text for this image may have been generated using AI.
Fig. 2: PinX1 inhibits the formation of migrasomes.
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Fig. 3: PinX1 promotes DDP sensitivity in NPC cells.
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Fig. 4: PinX1 promotes DDP sensitivity in NPC in vivo.
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Fig. 5: PinX1 binds to and inhibits the key protein Rab11a involved in vesicle secretion.
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Fig. 6: PinX1 interacts with Rab11a.
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Fig. 7: PinX1 inhibits the formation of migrasomes through Rab11a.
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Fig. 8: PinX1 enhances DDP sensitivity in NPC cells by inhibiting Rab11a and migrasome formation.
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Fig. 9: PinX1 promotes proteasomal degradation of Rab11a, and PinX1‑bound RanBP2 mediates SUMO2 modification and ubiquitination of Rab11a.
The alternative text for this image may have been generated using AI.
Fig. 10: PinX1 recruits RanBP2 to enhance Rab11a SUMOylation, leading to the degradation of Rab11a.
The alternative text for this image may have been generated using AI.
Fig. 11: PinX1 regulates the metabolic function of NPC cells by migrasome-mediated transfer of damaged mitochondria.
The alternative text for this image may have been generated using AI.
Fig. 12: The molecular mechanism model by which PinX1 regulates migrasome formation through Rab11a SUMOylation to promote DDP resistance in NPC.
The alternative text for this image may have been generated using AI.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Chen YP, Chan ATC, Le QT, Blanchard P, Sun Y, Ma J. Nasopharyngeal carcinoma. Lancet. 2019;394:64–80.

    Article  PubMed  Google Scholar 

  2. Jiromaru R, Nakagawa T, Yasumatsu R. Advanced nasopharyngeal carcinoma: current and emerging treatment options. Cancer Manag Res. 2022;14:2681–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Yoshizaki T, Kondo S, Murono S, Endo K, Tsuji A, Nakanishi Y, et al. Progress and controversy for the role of chemotherapy in nasopharyngeal carcinoma. Jpn J Clin Oncol. 2015;45:244–7.

    Article  PubMed  Google Scholar 

  4. Guan S, Wei J, Huang L, Wu L. Chemotherapy and chemo-resistance in nasopharyngeal carcinoma. Eur J Med Chem. 2020;207:112758.

    Article  CAS  PubMed  Google Scholar 

  5. Yu S, Yu L. Migrasome biogenesis and functions. FEBS J. 2022;289:7246–54.

    Article  CAS  PubMed  Google Scholar 

  6. Ding T, Ji J, Zhang W, Liu Y, Liu B, Han Y, et al. The phosphatidylinositol (4,5)-bisphosphate-Rab35 axis regulates migrasome formation. Cell Res. 2023;33:617–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Liang H, Ma X, Zhang Y, Liu Y, Liu N, Zhang W, et al. The formation of migrasomes is initiated by the assembly of sphingomyelin synthase 2 foci at the leading edge of migrating cells. Nat Cell Biol. 2023;25:1173–84.

    Article  CAS  PubMed  Google Scholar 

  8. Dharan R, Huang Y, Cheppali SK, Goren S, Shendrik P, Wang W, et al. Tetraspanin 4 stabilizes membrane swellings and facilitates their maturation into migrasomes. Nat Commun. 2023;14:1037.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Zhang X, Yao L, Meng Y, Li B, Yang Y, Gao F. Migrasome: a new functional extracellular vesicle. Cell Death Discov. 2023;9:381.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Hu M, Li T, Ma X, Liu S, Li C, Huang Z, et al. Macrophage lineage cells-derived migrasomes activate complement-dependent blood-brain barrier damage in cerebral amyloid angiopathy mouse model. Nat Commun. 2023;14:3945.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Li T, Su X, Lu P, Kang X, Hu M, Li C, et al. Bone marrow mesenchymal stem cell-derived dermcidin-containing migrasomes enhance LC3-associated phagocytosis of pulmonary macrophages and protect against post-stroke pneumonia. Adv Sci. 2023;10:e2206432.

    Article  Google Scholar 

  12. Jin P, Jiang J, Zhou L, Huang Z, Nice EC, Huang C, et al. Mitochondrial adaptation in cancer drug resistance: prevalence, mechanisms, and management. J Hematol Oncol. 2022;15:97.

    Article  PubMed  PubMed Central  Google Scholar 

  13. He Y, Ji Z, Gong Y, Fan L, Xu P, Chen X, et al. Numb/Parkin-directed mitochondrial fitness governs cancer cell fate via metabolic regulation of histone lactylation. Cell Rep. 2023;42:112033.

    Article  CAS  PubMed  Google Scholar 

  14. Saito K, Zhang Q, Yang H, Yamatani K, Ai T, Ruvolo V, et al. Exogenous mitochondrial transfer and endogenous mitochondrial fission facilitate AML resistance to OxPhos inhibition. Blood Adv. 2021;5:4233–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Jiao H, Jiang D, Hu X, Du W, Ji L, Yang Y, et al. Mitocytosis, a migrasome-mediated mitochondrial quality-control process. Cell. 2021;184:2896–2910 e2813.

    Article  CAS  PubMed  Google Scholar 

  16. Wang YQ, Wu DH, Wei D, Shen JY, Huang ZW, Liang XY, et al. TEAD4 is a master regulator of high-risk nasopharyngeal carcinoma. Sci Adv. 2023;9:eadd0960.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Yan L, Zhang T, Wang K, Chen Z, Yang Y, Shan B, et al. SENP1 prevents steatohepatitis by suppressing RIPK1-driven apoptosis and inflammation. Nat Commun. 2022;13:7153.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lai XF, Shen CX, Wen Z, Qian YH, Yu CS, Wang JQ, et al. PinX1 regulation of telomerase activity and apoptosis in nasopharyngeal carcinoma cells. J Exp Clin Cancer Res. 2012;31:12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Tian W, Lei N, Zhou J, Chen M, Guo R, Qin B, et al. Extracellular vesicles in ovarian cancer chemoresistance, metastasis, and immune evasion. Cell Death Dis. 2022;13:64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Marie PP, Fan SJ, Mason J, Wells A, Mendes CC, Wainwright SM, et al. Accessory ESCRT-III proteins are conserved and selective regulators of Rab11a-exosome formation. J Extracell Vesicles. 2023;12:e12311.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Jansen LR, Welch MA, Plant LD, Baro DJ. Crosstalk between PKA and PIAS3 regulates cardiac Kv4 channel SUMOylation. Cell Commun Signal. 2024;22:422.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Han D, Wang L, Jiang S, Yang Q. The ubiquitin-proteasome system in breast cancer. Trends Mol Med. 2023;29:599–621.

    Article  CAS  PubMed  Google Scholar 

  23. Liu X, Liu J, Xiao W, Zeng Q, Bo H, Zhu Y, et al. SIRT1 regulates N(6) -methyladenosine RNA modification in hepatocarcinogenesis by inducing RANBP2-dependent FTO SUMOylation. Hepatology. 2020;72:2029–50.

    Article  CAS  PubMed  Google Scholar 

  24. Zhang B, Li J, Wang Y, Liu X, Yang X, Liao Z, et al. Deubiquitinase USP7 stabilizes KDM5B and promotes tumor progression and cisplatin resistance in nasopharyngeal carcinoma through the ZBTB16/TOP2A axis. Cell Death Differ. 2024;31:309–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zampieri LX, Silva-Almeida C, Rondeau JD, Sonveaux P. Mitochondrial transfer in cancer: a comprehensive review. International J Mol Sci. 2021;22:3245.

  26. Deng S, Wu Y, Huang S, Yang X. Novel insights into the roles of migrasome in cancer. Discov Oncol. 2024;15:166.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhang R, Peng J, Zhang Y, Zheng K, Chen Y, Liu L, et al. Pancreatic cancer cell-derived migrasomes promote cancer progression by fostering an immunosuppressive tumor microenvironment. Cancer Lett. 2024;605:217289.

    Article  CAS  PubMed  Google Scholar 

  28. Qin Y, Yang J, Liang C, Liu J, Deng Z, Yan B, et al. Pan-cancer analysis identifies migrasome-related genes as a potential immunotherapeutic target: a bulk omics research and single cell sequencing validation. Front Immunol. 2022;13:994828.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kang J, Park JH, Kong JS, Kim MJ, Lee SS, Park S, et al. PINX1 promotes malignant transformation of thyroid cancer through the activation of the AKT/MAPK/beta-catenin signaling pathway. Am J Cancer Res. 2021;11:5485–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Hou P, Li H, Yong H, Chen F, Chu S, Zheng J, et al. PinX1 represses renal cancer angiogenesis via the mir-125a-3p/VEGF signaling pathway. Angiogenesis. 2019;22:507–19.

    Article  CAS  PubMed  Google Scholar 

  31. Shi M, Cao M, Song J, Liu Q, Li H, Meng F, et al. PinX1 inhibits the invasion and metastasis of human breast cancer via suppressing NF-kappaB/MMP-9 signaling pathway. Mol Cancer. 2015;14:66.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Yu C, Chen F, Wang X, Cai Z, Yang M, Zhong Q, et al. Pin2 telomeric repeat factor 1-interacting telomerase inhibitor 1 (PinX1) inhibits nasopharyngeal cancer cell stemness: implication for cancer progression and therapeutic targeting. J Exp Clin cancer Res: Cr. 2020;39:31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Guo RJ, Cao YF, Li EM, Xu LY. Multiple functions and dual characteristics of RAB11A in cancers. Biochim Biophys Acta Rev Cancer. 2023;1878:188966.

    Article  CAS  PubMed  Google Scholar 

  34. Yoshida K, Htike K, Eguchi T, Kawai H, Eain HS, Tran MT, et al. Rab11 suppresses head and neck carcinoma by regulating EGFR and EpCAM exosome secretion. J Oral Biosci. 2024;66:205–16.

    Article  CAS  PubMed  Google Scholar 

  35. Mason JD, Marks E, Fan SJ, McCormick K, Wilson C, Harris AL, et al. Stress-induced Rab11a-exosomes induce amphiregulin-mediated cetuximab resistance in colorectal cancer. J Extracell Vesicles. 2024;13:e12465.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Bai S, Hou W, Yao Y, Meng J, Wei Y, Hu F, et al. Exocyst controls exosome biogenesis via Rab11a. Mol Ther Nucleic acids. 2022;27:535–46.

    Article  CAS  PubMed  Google Scholar 

  37. Han ZJ, Feng YH, Gu BH, Li YM, Chen H. The post-translational modification, SUMOylation, and cancer (Review). Int J Oncol. 2018;52:1081–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Desgraupes S, Etienne L, Arhel NJ. RANBP2 evolution and human disease. FEBS Lett. 2023;597:2519–33.

    Article  CAS  PubMed  Google Scholar 

  39. Li J, Su L, Jiang J, Wang YE, Ling Y, Qiu Y, et al. RanBP2/Nup358 mediates sumoylation of STAT1 and antagonizes interferon-alpha-mediated antiviral innate immunity. Int J Mol Sci. 2023;25:299.

  40. Qian L, Liang Z, Wang Z, Wang J, Li X, Zhao J, et al. Cellular gp96 upregulates AFP expression by blocking NR5A2 SUMOylation and ubiquitination in hepatocellular carcinoma. J Mol Cell Biol. 2023;15:mjad027.

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Funding

This work was supported by the National Natural Science Foundation of China (82573354), the Guangzhou Science and Technology Plan Project (202201020017), and Special Presidential Foundation of Zhujiang Hospital of Southern Medical University (yzjj2024ms08).

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  1. These authors contributed equally: Juan Zhang, Junqi Wang, Tingfeng Liang.

Authors and Affiliations

  1. Department of Otorhinolaryngology Head and Neck Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China

    Juan Zhang, Tingfeng Liang, Fang Chen, Zhenchao Zhu, Yong He, Xueyong Hu, Jing Li, Shuaijun Chen & Chaosheng Yu

  2. Department of Otorhinolaryngology Head and Neck Surgery, Luoyang Key Laboratory of Genetic Research, Diagnosis and Treatment of Auditory Function Disorders, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China

    Junqi Wang

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Contributions

Conceptualization: SC, CY. Data curation and Validation: FC, ZZ. Methodology and Formal analysis: YH, XH, JL. Writing – original draft: JZ, JW, TL. Writing – review & editing: JZ, JW, TL. All authors read and approved the final manuscript.

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Correspondence to Shuaijun Chen or Chaosheng Yu.

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Zhang, J., Wang, J., Liang, T. et al. PinX1 inhibits migrasomes-mediated mitochondrial transfer to confer cisplatin sensitivity in nasopharyngeal carcinoma. Oncogene (2026). https://doi.org/10.1038/s41388-026-03741-9

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