Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Cancer associated fibroblast secreted miR-432-5p targets CHAC1 to inhibit ferroptosis and promote acquired chemoresistance in prostate cancer

Abstract

Prostate cancer (PCa) ranks as the sixth most serious male malignant disease globally. While docetaxel (DTX) chemotherapy is the standard treatment for advanced PCa patients with distant metastasis, some individuals exhibit insensitivity or resistance to DTX. Cancer-associated fibroblasts (CAFs) play a pivotal role as stromal cells within the tumor microenvironment, influencing tumor development, progression, and drug resistance through exosomes. Ferroptosis, a novel form of programmed cell death, is characterized by intracellular iron accumulation that triggers lipid peroxidation, ultimately leading to cell demise. To delve into the potential mechanisms of chemotherapy resistance in prostate cancer, our research delved into the impact of CAF-derived exosomes on ferroptosis. Our findings revealed that CAF exosomes hindered the buildup of lipid reactive oxygen species (ROS) in prostate cancer cells induced by erastin, as well as mitigated erastin-induced mitochondrial damage, thereby impeding iron-induced cell death in prostate cancer cells. Furthermore, miR-432-5p was identified to diminish glutathione (GSH) consumption by targeting CHAC1, consequently inhibiting ferroptosis in prostate cancer cells. Our study found that miR-432-5p, originating from cancer-associated fibroblast (CAF) exosomes, suppresses ferroptosis by targeting CHAC1, thereby increasing resistance to docetaxel (DTX) in PCa. This research introduces a novel approach to address resistance to DTX.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Identification of NF and CAF.
Fig. 2: CAF-Exos promotes the proliferation of PCa cells.
Fig. 3: Differential expression of miRNA in exosomes.
Fig. 4: miR-432-5p inhibits ferroptosis in PCa cells.
Fig. 5: Predicting the target gene of miR-432-5p in PCa cells.
Fig. 6: miR-432-5p inhibits ferroptosis in PCa cells by down-regulating the expression of CHAC1.
Fig. 7: DTX promotes the secretion of miR-432-5p by CAF.
Fig. 8: Role of miR-432-5p in regulating PCa growth and DTX sensitivity in vivo.

Similar content being viewed by others

Data availability

All data are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the corresponding authors.

References

  1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72:7–33.

    Article  PubMed  Google Scholar 

  2. Cornford P, van den Bergh RCN, Briers E, Van den Broeck T, Cumberbatch MG, De Santis M, et al. EAU-EANM-ESTRO-ESUR-SIOG Guidelines on Prostate Cancer. Part II-2020 update: Treatment of Relapsing and Metastatic Prostate Cancer. Eur Urol. 2021;79:263–82.

    Article  CAS  PubMed  Google Scholar 

  3. Rizzo M. Mechanisms of docetaxel resistance in prostate cancer: the key role played by miRNAs. Biochim Biophys Acta Rev Cancer. 2021;1875:188481.

    Article  CAS  PubMed  Google Scholar 

  4. Heidenreich A, Bastian PJ, Bellmunt J, Bolla M, Joniau S, van der Kwast T, et al. EAU guidelines on prostate cancer. Part II: treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol. 2014;65:467–79.

    Article  CAS  PubMed  Google Scholar 

  5. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

    Article  CAS  PubMed  Google Scholar 

  6. Pavlova NN, Thompson CB. The emerging hallmarks of cancer metabolism. Cell Metab. 2016;23:27–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Chen DS, Mellman I. Elements of cancer immunity and the cancer-immune set point. Nature. 2017;541:321–30.

    Article  CAS  PubMed  Google Scholar 

  8. Strasser A, Vaux DL. Cell death in the origin and treatment of cancer. Mol Cell. 2020;78:1045–54.

    Article  CAS  PubMed  Google Scholar 

  9. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Mou Y, Wang J, Wu J, He D, Zhang C, Duan C, et al. Ferroptosis, a new form of cell death: opportunities and challenges in cancer. J Hematol Oncol. 2019;12:34.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, et al. Regulation of ferroptotic cancer cell death by GPX4. Cell. 2014;156:317–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wang M, Zhao J, Zhang L, Wei F, Lian Y, Wu Y, et al. Role of tumor microenvironment in tumorigenesis. J Cancer. 2017;8:761–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Giraldo NA, Sanchez-Salas R, Peske JD, Vano Y, Becht E, Petitprez F, et al. The clinical role of the TME in solid cancer. Br J Cancer. 2019;120:45–53.

    Article  PubMed  Google Scholar 

  14. Liu T, Han C, Wang S, Fang P, Ma Z, Xu L, et al. Cancer-associated fibroblasts: an emerging target of anti-cancer immunotherapy. J Hematol Oncol. 2019;12:86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Bu L, Baba H, Yoshida N, Miyake K, Yasuda T, Uchihara T, et al. Biological heterogeneity and versatility of cancer-associated fibroblasts in the tumor microenvironment. Oncogene. 2019;38:4887–901.

    Article  CAS  PubMed  Google Scholar 

  16. Fiori ME, Di Franco S, Villanova L, Bianca P, Stassi G, De Maria R. Cancer-associated fibroblasts as abettors of tumor progression at the crossroads of EMT and therapy resistance. Mol Cancer. 2019;18:70.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Joshi RS, Kanugula SS, Sudhir S, Pereira MP, Jain S, Aghi MK. The role of cancer-associated fibroblasts in tumor progression. Cancers. 2021;13:1399

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Hinshaw DC, Shevde LA. The tumor microenvironment innately modulates cancer progression. Cancer Res. 2019;79:4557–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ostrowski M, Carmo NB, Krumeich S, Fanget I, Raposo G, Savina A, et al. Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat Cell Biol. 2010;12:19–30.

    Article  CAS  PubMed  Google Scholar 

  20. Balaj L, Lessard R, Dai L, Cho YJ, Pomeroy SL, Breakefield XO, et al. Tumour microvesicles contain retrotransposon elements and amplified oncogene sequences. Nat Commun. 2011;2:180.

    Article  PubMed  Google Scholar 

  21. Mathivanan S, Ji H, Simpson RJ. Exosomes: extracellular organelles important in intercellular communication. J Proteom. 2010;73:1907–20.

    Article  CAS  Google Scholar 

  22. Zhang H, Deng T, Liu R, Bai M, Zhou L, Wang X, et al. Exosome-delivered EGFR regulates liver microenvironment to promote gastric cancer liver metastasis. Nat Commun. 2017;8:15016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sun Z, Shi K, Yang S, Liu J, Zhou Q, Wang G, et al. Effect of exosomal miRNA on cancer biology and clinical applications. Mol Cancer. 2018;17:147.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Shan G, Zhou X, Gu J, Zhou D, Cheng W, Wu H, et al. Downregulated exosomal microRNA-148b-3p in cancer associated fibroblasts enhance chemosensitivity of bladder cancer cells by downregulating the Wnt/β-catenin pathway and upregulating PTEN. Cell Oncol. 2021;44:45–59.

    Article  CAS  Google Scholar 

  25. Zhang H, Deng T, Liu R, Ning T, Yang H, Liu D, et al. CAF secreted miR-522 suppresses ferroptosis and promotes acquired chemo-resistance in gastric cancer. Mol Cancer. 2020;19:43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Li J, Cao F, Yin HL, Huang ZJ, Lin ZT, Mao N, et al. Ferroptosis: past, present and future. Cell Death Dis. 2020;11:88.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Dixon SJ. Ferroptosis: bug or feature? Immunol Rev. 2017;277:150–7.

    Article  CAS  PubMed  Google Scholar 

  28. Guo J, Xu B, Han Q, Zhou H, Xia Y, Gong C, et al. Ferroptosis: a novel anti-tumor action for cisplatin. Cancer Res Treat. 2018;50:445–60.

    Article  CAS  PubMed  Google Scholar 

  29. Sun X, Niu X, Chen R, He W, Chen D, Kang R, et al. Metallothionein-1G facilitates sorafenib resistance through inhibition of ferroptosis. Hepatology. 2016;64:488–500.

    Article  CAS  PubMed  Google Scholar 

  30. Long KB, Collier AI, Beatty GL. Macrophages: key orchestrators of a tumor microenvironment defined by therapeutic resistance. Mol Immunol. 2019;110:3–12.

    Article  CAS  PubMed  Google Scholar 

  31. Quail DF, Bowman RL, Akkari L, Quick ML, Schuhmacher AJ, Huse JT, et al. The tumor microenvironment underlies acquired resistance to CSF-1R inhibition in gliomas. Science. 2016;352:aad3018.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Wang W, Green M, Choi JE, Gijón M, Kennedy PD, Johnson JK, et al. CD8(+) T cells regulate tumour ferroptosis during cancer immunotherapy. Nature. 2019;569:270–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Zhou X, Zou L, Liao H, Luo J, Yang T, Wu J, et al. Abrogation of HnRNP L enhances anti-PD-1 therapy efficacy via diminishing PD-L1 and promoting CD8(+) T cell-mediated ferroptosis in castration-resistant prostate cancer. Acta Pharm Sin B. 2022;12:692–707.

    Article  CAS  PubMed  Google Scholar 

  34. Ghoochani A, Hsu EC, Aslan M, Rice MA, Nguyen HM, Brooks JD, et al. Ferroptosis inducers are a novel therapeutic approach for advanced prostate cancer. Cancer Res. 2021;81:1583–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. He S, Zhang M, Ye Y, Zhuang J, Ma X, Song Y, et al. ChaC glutathione specific γ-glutamylcyclotransferase 1 inhibits cell viability and increases the sensitivity of prostate cancer cells to docetaxel by inducing endoplasmic reticulum stress and ferroptosis. Exp Ther Med. 2021;22:997.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Jiang X, Guo S, Wang S, Zhang Y, Chen H, Wang Y, et al. EIF4A3-Induced circARHGAP29 promotes aerobic glycolysis in docetaxel-resistant prostate cancer through IGF2BP2/c-Myc/LDHA signaling. Cancer Res. 2022;82:831–45.

    Article  CAS  PubMed  Google Scholar 

  37. Lin H, Wang Y, Wang P, Long F, Wang T. Mutual regulation between N6-methyladenosine (m6A) modification and circular RNAs in cancer: impacts on therapeutic resistance. Mol Cancer. 2022;21:148.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Chen J, Zhang Y, Zhang X, Zhao J, Ni Y, Zhu S, et al. Comparison of systemic treatments for metastatic castration-resistant prostate cancer after docetaxel failure: a systematic review and network meta-analysis. Front Pharmacol. 2021;12:789319.

    Article  CAS  PubMed  Google Scholar 

  39. Silva MM, Rocha CRR, Kinker GS, Pelegrini AL, Menck CFM. The balance between NRF2/GSH antioxidant mediated pathway and DNA repair modulates cisplatin resistance in lung cancer cells. Sci Rep. 2019;9:17639.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Rebollido-Rios R, Venton G, Sánchez-Redondo S, Iglesias IFC, Fournet G, González E, et al. Dual disruption of aldehyde dehydrogenases 1 and 3 promotes functional changes in the glutathione redox system and enhances chemosensitivity in nonsmall cell lung cancer. Oncogene. 2020;39:2756–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Qin X, Yan M, Wang X, Xu Q, Wang X, Zhu X, et al. Cancer-associated fibroblast-derived IL-6 promotes head and neck cancer progression via the osteopontin-NF-kappa B signaling pathway. Theranostics. 2018;8:921–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

The study is funded by Jiangsu Provincial Social Development Project (BE2021605).

Author information

Authors and Affiliations

Authors

Contributions

JZ and HBS participated in study design; JZ, TLY, and LM involved in data collection; JZ, and JJS performed research; JJS, JYL and LM performed the software; JZ, and LM involved in methodology and data analysis; J Z, JJS and HBS involved in manuscript preparation. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Sun Hongbin.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

All procedures were permitted by the Ethics Committee for the use of Experimental Animals of Nanjing First Hospital, Nanjing Medical University. This study was directed according to the Guidelines for the Care and Use of Laboratory Animals of the National Institutes of Health (NIH).

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhao, J., Shen, J., Mao, L. et al. Cancer associated fibroblast secreted miR-432-5p targets CHAC1 to inhibit ferroptosis and promote acquired chemoresistance in prostate cancer. Oncogene (2024). https://doi.org/10.1038/s41388-024-03057-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41388-024-03057-6

Search

Quick links