Skip to main content
SpringerLink
Log in

Brevilin A Inhibits Prostate Cancer Progression by Decreasing PAX5-Activated SOX4

  • Original Paper
  • Published:
Molecular Biotechnology Aims and scope Submit manuscript

Abstract

Brevilin A possesses inhibitory effects on the development of prostate cancer (PCa); however, the underlying mechanism remains unclear. The present work aims to analyze how Brevilin A regulates PCa cell malignancy. RNA expression of paired box 5 (PAX5) and SRY-box transcription factor 4 (SOX4) was analyzed by quantitative real-time polymerase chain reaction. Protein expression of PAX5, SOX4, and nuclear proliferation marker (Ki67) was detected by western blotting or immunohistochemistry assay. The viability, proliferation, apoptosis, and migratory and invasive abilities of PCa cells were investigated by cell counting kit-8 (CCK-8), 5-Ethynyl-2’-deoxyuridine (EdU), flow cytometry, and transwell assays, respectively. The association between PAX5 and SOX4 was identified by dual-luciferase reporter assay and chromatin immunoprecipitation assay. Xenograft mouse model assay was used to reveal the effect of Brevilin A on tumor tumorigenesis in vivo. PAX5 and SOX4 expression were upregulated in PCa tissues and cells relative to normal prostate tissues and human prostate epithelial cells. Brevilin A treatment inhibited PAX5 protein expression in PCa cells. Additionally, Brevilin A inhibited proliferation, migration and invasion and induced apoptosis of PCa cells, whereas these effects were attenuated after PAX5 overexpression. SOX4 was transcriptionally activated by PAX5, and its introduction partially relieved the inhibitory effects of PAX5 knockdown on PCa cell malignancy. Moreover, Brevilin A delayed tumor formation in vivo. Brevilin A inhibited PCa progression by regulating SOX4 expression in a PAX5-dependent manner, providing a promising anti-tumor drug for PCa.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Availability of Data and Materials

The analyzed data sets generated during the present study are available from the corresponding author on reasonable request.

References

  1. Wasim, S., Lee, S. Y., & Kim, J. (2022). Complexities of prostate cancer. International Journal of Molecular Sciences, 23(22), 14257.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Wang, G., Zhao, D., Spring, D. J., & DePinho, R. A. (2018). Genetics and biology of prostate cancer. Genes and Development., 32(17–18), 1105–1140.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Valdman, A., Nordenskjöld, A., Fang, X., et al. (2003). Mutation analysis of the BRG1 gene in prostate cancer clinical samples. International Journal of Oncology, 22(5), 1003–1007.

    CAS  PubMed  Google Scholar 

  4. Daniyal, M., Siddiqui, Z. A., Akram, M., Asif, H. M., Sultana, S., & Khan, A. (2014). Epidemiology, etiology, diagnosis and treatment of prostate cancer. Asian Pacific journal of cancer prevention : APJCP., 15(22), 9575–9578.

    Article  PubMed  Google Scholar 

  5. Ohlmann, C. (2023). Hormone-sensitive prostate cancer. Urologie (Heidelberg, Germany)., 62(4), 345–346.

    PubMed  Google Scholar 

  6. Teo, M. Y., Rathkopf, D. E., & Kantoff, P. (2019). Treatment of advanced prostate cancer. Annual Review of Medicine., 70, 479–499.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Evans, A. J. (2018). Treatment effects in prostate cancer. Modern Pathology., 31(S1), S110-121.

    Article  PubMed  Google Scholar 

  8. Chen, X., Du, Y., Nan, J., et al. (2013). Brevilin A, a novel natural product, inhibits janus kinase activity and blocks STAT3 signaling in cancer cells. PLoS ONE, 8(5), e63697.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Qu, Z., Lin, Y., Mok, D. K., Bian, Q., Tai, W. C., & Chen, S. (2020). Brevilin A, a natural sesquiterpene lactone inhibited the growth of triple-negative breast cancer cells via Akt/mTOR and STAT3 signaling pathways. OncoTargets and Therapy., 13, 5363–5373.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Khan, M., Maryam, A., Saleem, M. Z., et al. (2020). Brevilin A induces ROS-dependent apoptosis and suppresses STAT3 activation by direct binding in human lung cancer cells. Journal of Cancer., 11(13), 3725–3735.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. You, P., Wu, H., Deng, M., Peng, J., Li, F., & Yang, Y. (2018). Brevilin A induces apoptosis and autophagy of colon adenocarcinoma cell CT26 via mitochondrial pathway and PI3K/AKT/mTOR inactivation. Biomedicine and Pharmacotherapy, 98, 619–625.

    Article  CAS  PubMed  Google Scholar 

  12. Liu, R., Qu, Z., Lin, Y., Lee, C. S., Tai, W. C., & Chen, S. (2019). Brevilin A induces cell cycle arrest and apoptosis in nasopharyngeal carcinoma. Frontiers in Pharmacology., 10, 594.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lee, D., Kwak, H. J., Kim, B. H., et al. (2022). Brevilin A isolated from centipeda minima induces apoptosis in human gastric cancer cells via an extrinsic apoptotic signaling pathway. Plants (Basel, Switzerland)., 11(13), 1658.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. You, P., Tang, L., Zhu, Y., & Tian, Y. (2023). Brevilin A shows an anti-tumor role in prostate cancer via the lncRNA H19/miR-194/E2F3 signaling pathway. Aging, 15(10), 4411–4428.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Gu, Z., Churchman, M. L., Roberts, K. G., et al. (2019). PAX5-driven subtypes of B-progenitor acute lymphoblastic leukemia. Nature Genetics., 51(2), 296–307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Fouad, F. M., & Eid, J. I. (2023). PAX5 fusion genes in acute lymphoblastic leukemia: A literature review. Medicine, 102(20), e33836.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Leblanc, N., Harquail, J., Crapoulet, N., Ouellette, R. J., & Robichaud, G. A. (2018). Pax-5 inhibits breast cancer proliferation through MiR-215 up-regulation. Anticancer Research., 38(9), 5013–5026.

    Article  CAS  PubMed  Google Scholar 

  18. Wu, X., Xiao, Y., Zhou, Y., Zhou, Z., & Yan, W. (2019). LncRNA FOXP4-AS1 is activated by PAX5 and promotes the growth of prostate cancer by sequestering miR-3184-5p to upregulate FOXP4. Cell Death and Disease., 10(7), 472.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Zhang, N., Li, Z., Bai, F., & Zhang, S. (2019). PAX5-induced upregulation of IDH1-AS1 promotes tumor growth in prostate cancer by regulating ATG5-mediated autophagy. Cell Death and Disease., 10(10), 734.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Penzo-Méndez, A. I. (2010). Critical roles for SoxC transcription factors in development and cancer. The International Journal of Biochemistry and Cell Biology., 42(3), 425–428.

    Article  PubMed  Google Scholar 

  21. Ahmed, E. A., & Alzahrani, A. M. (2023). SOXC transcription factors as diagnostic biomarkers and therapeutic targets for arthritis. International Journal of Molecular Sciences., 24(4), 4215.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Liu, Y., Zeng, S., Jiang, X., Lai, D., & Su, Z. (2017). SOX4 induces tumor invasion by targeting EMT-related pathway in prostate cancer. Tumour biology: The Journal of the International Society for Oncodevelopmental Biology and Medicine., 39(5), 1010428317694539.

    Article  PubMed  Google Scholar 

  23. Wang, L., Zhang, J., Yang, X., et al. (2013). SOX4 is associated with poor prognosis in prostate cancer and promotes epithelial–mesenchymal transition in vitro. Prostate Cancer and Prostatic Diseases., 16(4), 301–307.

    Article  CAS  PubMed  Google Scholar 

  24. Huang, D. W., Huang, M., Lin, X. S., & Huang, Q. (2017). CD155 expression and its correlation with clinicopathologic characteristics, angiogenesis, and prognosis in human cholangiocarcinoma. OncoTargets and Therapy., 10, 3817–3825.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Ren, X., Chen, X., Zhang, X., et al. (2021). Immune microenvironment and response in prostate cancer using large population cohorts. Frontiers in Immunology., 12, 686809.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lee, M. M., Chan, B. D., Wong, W. Y., et al. (2020). Synthesis and evaluation of novel anticancer compounds derived from the natural product Brevilin A. ACS Omega, 5(24), 14586–14596.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Su, T., Wang, Y. P., Wang, X. N., et al. (2020). The JAK2/STAT3 pathway is involved in the anti-melanoma effects of brevilin A. Life Sciences., 241, 117169.

    Article  CAS  PubMed  Google Scholar 

  28. Wei, B., Hao, Z., Zheng, H., Qin, Y., Zhao, F., & Shi, L. (2022). Brevilin A inhibits VEGF-induced angiogenesis through ROS-dependent mitochondrial dysfunction. Oxidative Medicine and Cellular Longevity., 2022, 5888636.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Yu, J., Kim, S., Lee, N., et al. (2021). Pax5 negatively regulates osteoclastogenesis through downregulation of Blimp1. International Journal of Molecular Sciences., 22(4), 2097.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Benzina, S., Beauregard, A. P., Guerrette, R., et al. (2017). Pax-5 is a potent regulator of E-cadherin and breast cancer malignant processes. Oncotarget, 8(7), 12052–12066.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Benzina, S., Harquail, J., Guerrette, R., et al. (2016). Breast cancer malignant processes are regulated by Pax-5 through the disruption of FAK signaling pathways. Journal of Cancer., 7(14), 2035–2044.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Harquail, J., LeBlanc, N., Landry, C., Crapoulet, N., & Robichaud, G. A. (2018). Pax-5 inhibits NF-κB activity in breast cancer cells through IKKε and miRNA-155 effectors. Journal of Mammary Gland Biology and Neoplasia., 23(3), 177–187.

    Article  PubMed  Google Scholar 

  33. Sun, D., Li, F., Liu, L., et al. (2022). PSMA3-AS1 induced by transcription factor PAX5 promotes cholangiocarcinoma proliferation, migration and invasion by sponging miR-376a-3p to up-regulate LAMC1. Aging, 14(1), 509–525.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Liu, S. L., Cai, C., Yang, Z. Y., et al. (2021). DGCR5 is activated by PAX5 and promotes pancreatic cancer via targeting miR-3163/TOP2A and activating Wnt/β-catenin pathway. International Journal of Biological Sciences., 17(2), 498–513.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Song, H. R., Guo, X. B., Duan, Y., Meng, H. Y., & Wang, Z. Y. (2021). PAX5-induced upregulation of LINC01194 exerts oncogenic properties by regulating GOLPH3 expression via miR-486-5p in prostate cancer. European Review for Medical and Pharmacological Sciences., 25(6), 2528–2541.

    PubMed  Google Scholar 

  36. Liu, H., Wu, Z., Zhou, H., et al. (2019). The SOX4/miR-17-92/RB1 axis promotes prostate cancer progression. Neoplasia (New York, NY)., 21(8), 765–776.

    Article  Google Scholar 

Download references

Funding

None.

Author information

Authors and Affiliations

  1. Department of Urology, Xiantao First People’s Hospital, No. 29, Mianzhou Avenue, Nancheng New District, Xiantao, 433000, Hubei, China

    Xinxiang Que, Desheng Chen, Zhen Nie & Peng Chen

  2. Ultrasound Imaging Department, Xiantao First People’s Hospital, Xiantao, 433000, Hubei, China

    Jianqun Fan

Authors
  1. Xinxiang Que
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jianqun Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Desheng Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhen Nie
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Peng Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization and methodology: Jianqun Fan and Desheng Chen; formal analysis and data curation: Zhen Nie, Peng Chen, and Desheng Chen; validation and investigation: Xinxiang Que and Jianqun Fan; writing—original draft preparation and writing—review and editing: Xinxiang Que, Jianqun Fan, and Desheng Chen; approval of final manuscript: all authors.

Corresponding author

Correspondence to Peng Chen.

Ethics declarations

Conflict of interest

The authors declare that they have no financial or non-financial conflicts of interest.

Ethics approval and consent to participate

The present study was approved by the ethical review committee of Xiantao First People’s Hospital. Written informed consent was obtained from all enrolled patients.

Consent for publication

Patients agree to participate in this work.

Additional information

Publisher's Note

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

Supplementary Information

Below is the link to the electronic supplementary material.

12033_2024_1183_MOESM1_ESM.tif

Supplementary file1 Figure S1 Analysis of weight between the treatment group and the control group throughout the experimental period (TIF 113 KB)

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

Que, X., Fan, J., Chen, D. et al. Brevilin A Inhibits Prostate Cancer Progression by Decreasing PAX5-Activated SOX4. Mol Biotechnol (2024). https://doi.org/10.1007/s12033-024-01183-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12033-024-01183-w

Keywords

Search

Navigation