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.

Klotho-beta attenuates Rab8a-mediated exosome regulation and promotes prostate cancer progression

Oncogene volume 42, pages 2801–2815 (2023)Cite this article

Subjects

Abstract

Tumor-secreted exosomes have a wide range of effects on the growth, metastasis, and drug resistance of cancer cells. However, whether and how the molecular mechanisms that regulate the secretion of exosomes could affect tumor progression remains poorly understood. Klotho beta (KLB) has been reported dysregulated in prostate cancer, but its function remains unknown. Herein, we first determined that KLB was upregulated in prostate cancer and its expression level was positively correlated with prostate cancer malignant phenotype both in vitro and in vivo. Intriguingly, KLB overexpression could impair the release of exosomes and cause the intracellular accumulation of multivesicular bodies (MVBs) in prostate cancer cells. Mechanistically, KLB attenuated exosomes secretion through a Rab8a-dependent pathway. Rab8a was downregulated in KLB overexpressing cells whereas overexpression of Rab8a could rescue the impaired release of exosomes and attenuate the KLB-induced malignant phenotype of prostate cancer both in vitro and in vivo. Taken together, this study has unveiled the tumor-promoting role of KLB mediated by its regulation on exosomes secretion through a Rab8a-dependent mechanism. These findings could be exploited to develop novel theranostic targets for prostate cancer.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

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

Fig. 1: High expression of KLB is associated with prostate cancer progression.
Fig. 2: KLB is essential for proliferation and migration of prostate cancer cells.
Fig. 3: Activation of FGFR4-mTOR signaling pathway by KLB, which is inhibited by the mTOR inhibitor rapamycin.
Fig. 4: KLB mediates exosomes secretion and the MVBs distribution in prostate cancer cells.
Fig. 5: Reciprocal regulation and interaction of KLB with Rab8a.
Fig. 6: Overexpression of Rab8a attenuates KLB-induced proliferation of prostate cancer cells.

Similar content being viewed by others

Data availability

All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data underlying the study are available on request to the authors.

References

  1. Culp MB, Soerjomataram I, Efstathiou JA, Bray F, Jemal A. Recent global patterns in prostate cancer incidence and mortality rates. Eur Urol. 2020;77:38–52.

    Article  PubMed  Google Scholar 

  2. Teo MY, Rathkopf DE, Kantoff P. Treatment of advanced prostate cancer. Annu Rev Med. 2019;70:479–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Moussa M, Papatsoris A, Abou Chakra M, Sryropoulou D, Dellis A. Pharmacotherapeutic strategies for castrate-resistant prostate cancer. Expert Opin Pharmacother. 2020;21:1431–48.

    Article  CAS  PubMed  Google Scholar 

  4. Vellky JE, Ricke WA. Development and prevalence of castration-resistant prostate cancer subtypes. Neoplasia. 2020;22:566–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Lee S, Choi J, Mohanty J, Sousa LP, Tome F, Pardon E, et al. Structures of β-klotho reveal a 'zip code'-like mechanism for endocrine FGF signalling. Nature. 2018;553:501–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kuro-o M. Klotho and βKlotho. Adv Exp Med Biol. 2012;728:25–40.

    Article  CAS  PubMed  Google Scholar 

  7. Feng S, Wang J, Zhang Y, Creighton CJ, Ittmann M. FGF23 promotes prostate cancer progression. Oncotarget. 2015;6:17291–301.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Nagamatsu H, Teishima J, Goto K, Shikuma H, Kitano H, Shoji K, et al. FGF19 promotes progression of prostate cancer. Prostate. 2015;75:1092–101.

    Article  CAS  PubMed  Google Scholar 

  9. Feng S, Dakhova O, Creighton CJ, Ittmann M. Endocrine fibroblast growth factor FGF19 promotes prostate cancer progression. Cancer Res. 2013;73:2551–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kotepui K, Kotepui M, Piwkham D, Songsri A, Charoenkijkajorn L, Sattaso A, et al. Increased expression of β-klotho is associated with axillary lymph node metastasis in breast cancer: An Immunohistological study. J Med Assoc Thail. 2019;102:1060–4.

    Google Scholar 

  11. Poh W, Wong W, Ong H, Aung MO, Lim SG, Chua BT, et al. Klotho-beta overexpression as a novel target for suppressing proliferation and fibroblast growth factor receptor-4 signaling in hepatocellular carcinoma. Mol Cancer. 2012;11:14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Li F, Li X, Li Z, Ji W, Lu S, Xia W. βKlotho is identified as a target for theranostics in non-small cell lung cancer. Theranostics. 2019;9:7474–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Peinado H, Zhang H, Matei IR, Costa-Silva B, Hoshino A, Rodrigues G, et al. Pre-metastatic niches: organ-specific homes for metastases. Nat Rev Cancer. 2017;17:302–17.

    Article  CAS  PubMed  Google Scholar 

  14. Onishi K, Miyake M, Hori S, Onishi S, Iida K, Morizawa Y, et al. γ-Klotho is correlated with resistance to docetaxel in castration-resistant prostate cancer. Oncol Lett. 2020;19:2306–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Shenefelt DLM. FGFR4 and β-Klotho in Metastatic Prostate Cancer. Rice University ProQuest Dissertations Publishing; 2012. 1524890.

  16. Liu Z, Zhang H, Ding S, Qi S, Liu S, Sun D, et al. βKlotho inhibits androgen/androgen receptor‑associated epithelial‑mesenchymal transition in prostate cancer through inactivation of ERK1/2 signaling. Oncol Rep. 2018;40:217–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. van Niel G, Carter DRF, Clayton A, Lambert DW, Raposo G, Vader P. Challenges and directions in studying cell-cell communication by extracellular vesicles. Nat Rev Mol Cell Biol. 2022;23:369–82.

    Article  PubMed  Google Scholar 

  18. Cocucci E, Meldolesi J. Ectosomes and exosomes: shedding the confusion between extracellular vesicles. Trends Cell Biol. 2015;25:364–72.

    Article  CAS  PubMed  Google Scholar 

  19. McAndrews KM, Kalluri R. Mechanisms associated with biogenesis of exosomes in cancer. Mol Cancer. 2019;18:52.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Chen YD, Fang YT, Cheng YL, Lin CF, Hsu LJ, Wang SY, et al. Exophagy of annexin A2 via RAB11, RAB8A and RAB27A in IFN-γ-stimulated lung epithelial cells. Sci Rep. 2017;7:5676.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science. 2020;367:eaau6977.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Pathan M, Fonseka P, Chitti SV, Kang T, Sanwlani R, Van Deun J, et al. Vesiclepedia 2019: a compendium of RNA, proteins, lipids and metabolites in extracellular vesicles. Nucleic Acids Res. 2019;47:D516–9.

    Article  CAS  PubMed  Google Scholar 

  23. Möller A, Lobb RJ. The evolving translational potential of small extracellular vesicles in cancer. Nat Rev Cancer. 2020;20:697–709.

    Article  PubMed  Google Scholar 

  24. Zou W, Lai M, Zhang Y, Zheng L, Xing Z, Li T, et al. Exosome release is regulated by mTORC1. Adv Sci (Weinh). 2019;6:1801313.

    Article  PubMed  Google Scholar 

  25. Zhao S, Mi Y, Guan B, Zheng B, Wei P, Gu Y, et al. Tumor-derived exosomal miR-934 induces macrophage M2 polarization to promote liver metastasis of colorectal cancer. J Hematol Oncol. 2020;13:156.

    Article  PubMed  PubMed Central  Google Scholar 

  26. He L, Zhu W, Chen Q, Yuan Y, Wang Y, Wang J, et al. Ovarian cancer cell-secreted exosomal miR-205 promotes metastasis by inducing angiogenesis. Theranostics. 2019;9:8206–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Bobrie A, Krumeich S, Reyal F, Recchi C, Moita LF, Seabra MC, et al. Rab27a supports exosome-dependent and -independent mechanisms that modify the tumor microenvironment and can promote tumor progression. Cancer Res. 2012;72:4920–30.

    Article  CAS  PubMed  Google Scholar 

  28. Lancaster GI, Febbraio MA. Exosome-dependent trafficking of HSP70: a novel secretory pathway for cellular stress proteins. J Biol Chem. 2005;280:23349–55.

    Article  CAS  PubMed  Google Scholar 

  29. Zhang L, Yu D. Exosomes in cancer development, metastasis, and immunity. Biochim Biophys Acta Rev Cancer. 2019;1871:455–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Li F, Li Z, Han Q, Cheng Y, Ji W, Yang Y, et al. Enhanced autocrine FGF19/FGFR4 signaling drives the progression of lung squamous cell carcinoma, which responds to mTOR inhibitor AZD2104. Oncogene. 2020;39:3507–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Raudenska M, Balvan J, Masarik M. Crosstalk between autophagy inhibitors and endosome-related secretory pathways: a challenge for autophagy-based treatment of solid cancers. Mol Cancer. 2021;20:140.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Ao X, Zou L, Wu Y. Regulation of autophagy by the Rab GTPase network. Cell Death Differ. 2014;21:348–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Dupont N, Jiang S, Pilli M, Ornatowski W, Bhattacharya D, Deretic V. Autophagy-based unconventional secretory pathway for extracellular delivery of IL-1β. Embo J. 2011;30:4701–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Zhao H, Yang L, Baddour J, Achreja A, Bernard V, Moss T, et al. Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism. Elife. 2016;5:e10250.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Hao M, Yeo SK, Turner K, Harold A, Yang Y, Zhang X, et al. Autophagy blockade limits HER2+ breast cancer tumorigenesis by perturbing HER2 trafficking and promoting release via small extracellular vesicles. Dev Cell. 2021;56:341–55.e5.

    Article  CAS  PubMed  Google Scholar 

  36. Costa-Silva B, Aiello NM, Ocean AJ, Singh S, Zhang H, Thakur BK, et al. Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat Cell Biol. 2015;17:816–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Hoshino A, Costa-Silva B, Shen TL, Rodrigues G, Hashimoto A, Tesic Mark M, et al. Tumour exosome integrins determine organotropic metastasis. Nature. 2015;527:329–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Yang Y, Li CW, Chan LC, Wei Y, Hsu JM, Xia W, et al. Exosomal PD-L1 harbors active defense function to suppress T cell killing of breast cancer cells and promote tumor growth. Cell Res. 2018;28:862–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zhou J, Ben S, Xu T, Xu L, Yao X. Serum β-klotho is a potential biomarker in the prediction of clinical outcomes among patients with NSCLC. J Thorac Dis. 2021;13:3137–50.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Hori S, Miyake M, Onishi S, Tatsumi Y, Morizawa Y, Nakai Y, et al. Clinical significance of α‑ and β‑Klotho in urothelial carcinoma of the bladder. Oncol Rep. 2016;36:2117–25.

    Article  CAS  PubMed  Google Scholar 

  41. Katoh M. FGFR inhibitors: effects on cancer cells, tumor microenvironment and whole-body homeostasis (Review). Int J Mol Med. 2016;38:3–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Prieto-Dominguez N, Shull AY, Teng Y. Making way for suppressing the FGF19/FGFR4 axis in cancer. Future Med Chem. 2018;10:2457–70.

    Article  CAS  PubMed  Google Scholar 

  43. Haas AK, Fuchs E, Kopajtich R, Barr FA. A GTPase-activating protein controls Rab5 function in endocytic trafficking. Nat Cell Biol. 2005;7:887–93.

    Article  CAS  PubMed  Google Scholar 

  44. Peränen J. Rab8 GTPase as a regulator of cell shape. Cytoskeleton (Hoboken). 2011;68:527–39.

    Article  PubMed  Google Scholar 

  45. Nakajo A, Yoshimura S, Togawa H, Kunii M, Iwano T, Izumi A, et al. EHBP1L1 coordinates Rab8 and Bin1 to regulate apical-directed transport in polarized epithelial cells. J Cell Biol. 2016;212:297–306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Wang J, Morita Y, Mazelova J, Deretic D. The Arf GAP ASAP1 provides a platform to regulate Arf4- and Rab11-Rab8-mediated ciliary receptor targeting. Embo J. 2012;31:4057–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Choi J, Sung JY, Lee S, Yoo J, Rongo C, Kim YN, et al. Rab8 and Rabin8-mediated tumor formation by hyperactivated EGFR signaling via FGFR signaling. Int J Mol Sci. 2020;21:7770.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Chen B, Huang S, Pisanic Ii TR, Stark A, Tao Y, Cheng B, et al. Rab8 GTPase regulates Klotho-mediated inhibition of cell growth and progression by directly modulating its surface expression in human non-small cell lung cancer. EBioMedicine. 2019;49:118–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Baixauli F, López-Otín C, Mittelbrunn M. Exosomes and autophagy: coordinated mechanisms for the maintenance of cellular fitness. Front Immunol. 2014;5:403.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Verweij FJ, Balaj L, Boulanger CM, Carter D, Compeer EB, D'angelo G, et al. The power of imaging to understand extracellular vesicle biology in vivo. Nat Methods. 2021;18:1013–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Chairoungdua A, Smith DL, Pochard P, Hull M, Caplan MJ. Exosome release of β-catenin: a novel mechanism that antagonizes Wnt signaling. J Cell Biol. 2010;190:1079–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Teng Y, Ren Y, Hu X, Mu J, Samykutty A, Zhuang X, et al. MVP-mediated exosomal sorting of miR-193a promotes colon cancer progression. Nat Commun. 2017;8:14448.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Shao J, Yang X, Liu T, Zhang T, Xie QR, Xia W. Autophagy induction by SIRT6 is involved in oxidative stress-induced neuronal damage. Protein Cell. 2016;7:281–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Cheng Y, Zeng Q, Han Q, Xia W. Effect of pH, temperature and freezing-thawing on quantity changes and cellular uptake of exosomes. Protein Cell. 2019;10:295–9.

    Article  CAS  PubMed  Google Scholar 

  55. Zeng Q, Hong S, Wang X, Cheng Y, Sun J, Xia W. Regulation of exosomes secretion by low-intensity pulsed ultrasound in lung cancer cells. Exp Cell Res. 2019;383:111448.

    Article  CAS  PubMed  Google Scholar 

  56. Zhao Z, Wijerathne H, Godwin AK, Soper SA. Isolation and analysis methods of extracellular vesicles (EVs). Extracell Vesicles Circ Nucl Acids. 2021;2:80–103.

    CAS  PubMed  Google Scholar 

  57. Mehdiani A, Maier A, Pinto A, Barth M, Akhyari P, Lichtenberg A. An innovative method for exosome quantification and size measurement. J Vis Exp. 2015;95:50974.

    Google Scholar 

Download references

Acknowledgements

We thank Xinqiu Guo, Yanhua Zhu, and Mengyu Yan (Instrumental Analysis Center, Shanghai Jiao Tong University, Shanghai, China) for the technical support of TEM.

Funding

This work was supported by grants from Ministry of Science and Technology (2022YFC2702703), Science and Technology Commission of Shanghai Municipality (21ZR1433100), National Natural Science Foundation of China (81773115) and SJTU funding (YG2022ZD016, YG2017MS52).

Author information

Authors and Affiliations

  1. State Key Laboratory of Systems Medicine for Cancer, Renji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China

    Tingyu Wu, Yanshuang Zhang, Qing Han, Xin Lu, Yirui Cheng, Jiachen Chen & Weiliang Xia

  2. Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

    Jianjun Sha

Authors
  1. Tingyu Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yanshuang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Qing Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xin Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yirui Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jiachen Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jianjun Sha
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Weiliang Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

TW designed and performed experiments and wrote the paper. YZ and QH participated in writing the paper and the discussion of related experiments. YC and XL performed imaging analysis. JC participated in animal experiments. JS provided clinical samples and information. WX conceived and supervised the project, obtained the funding and proofed the writing.

Corresponding author

Correspondence to Weiliang Xia.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

For investigations on humans, ethics committee approval from School of Biomedical Engineering, Shanghai Jiao Tong University was obtained prior to the research (BME-2017032) and informed written consent of all participants were obtained. All animal studies were performed following the Institutional Ethics Committee of School of Biomedical Engineering, Shanghai Jiao Tong University (BME-2021013).

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

Wu, T., Zhang, Y., Han, Q. et al. Klotho-beta attenuates Rab8a-mediated exosome regulation and promotes prostate cancer progression. Oncogene 42, 2801–2815 (2023). https://doi.org/10.1038/s41388-023-02807-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-023-02807-2

Search

Advanced search

Quick links