Skip to main content

Advertisement

SpringerLink
Log in

Repurposing ketotifen as a therapeutic strategy for neuroendocrine prostate cancer by targeting the IL-6/STAT3 pathway

  • Research
  • Published:
Cellular Oncology Aims and scope Submit manuscript

Abstract

Purpose

Neuroendocrine prostate cancer (NEPC), a highly aggressive subtype of prostate cancer displaying resistance to hormone therapy, presents a poor prognosis and limited therapeutic options. Here, we aimed to find novel medication therapies for NEPC and explore the underlying mechanism.

Methods

A high-throughput drug screening utilizing an FDA-approved drug library was performed and ketotifen, an antihistamine agent, was identified as a potential therapeutic candidate for NEPC. The whole-transcriptome sequencing analysis was conducted to explore mechanism of ketotifen inhibitory in NEPC. Multiple cell biology and biochemistry experiments were performed to confirm the inhibitory effect of ketotifen in vitro. A spontaneous NEPC mice model (PBCre4:Ptenf/f;Trp53f/f;Rb1f/f) was used to reveal the inhibitory effect of ketotifen in vivo.

Results

Our in vitro experiments demonstrated that ketotifen effectively suppressed neuroendocrine differentiation, reduced cell viability, and reversed the lineage switch via targeting the IL-6/STAT3 pathway. Our in vivo results showed that ketotifen significantly prolonged overall survival and reduced the risk of distant metastases in NEPC mice model.

Conclusion

Our findings repurpose ketotifen for antitumor applications and endorse its clinical development for NEPC therapy, offering a novel and promising therapeutic strategy for this formidable cancer subtype.

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

Similar content being viewed by others

Data availability

All pertinent data and materials can be obtained from the corresponding author upon a reasonable request. The RNAseq data of LASCPC-01 cells treated with ketotifen or PBS was uploaded to the Gene Expression Omnibus database GSE225007.

Abbreviations

NEPC:

Neuroendocrine prostate cancer

FDA:

Food and Drug Administration

IL-6:

Interleukin 6

STAT3:

Signal transducer and activator of transcription 3

JAK:

Janus Kinase

AR:

Androgen receptor

EMT:

Epithelial-mesenchymal transition

PTEN:

Phosphatase and tensin homolog

TP53:

Tumor protein 53

RB1:

Retinoblastomal 1

MYCN:

V-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog

AKT1:

AKT Serine/Threonine Kinase 1

PBS:

Phosphate buffer saline

IHC:

Immunohistochemistry

H&E:

Hematoxylin-eosin

p-:

Phosphorylated

References

  1. W. Wang, J.I. Epstein, Am J Surg Pathol. 32(1), 65–71 (2008). https://doi.org/10.1097/PAS.0b013e318058a96b

    Article  PubMed  Google Scholar 

  2. Y. Wang, Y. Wang, X. Ci, S.Y.C. Choi, F. Crea, D. Lin, Y. Wang, Nature reviews. Urology 18, 581–596 (2021). https://doi.org/10.1038/s41585-021-00490-0

    Article  PubMed  Google Scholar 

  3. E.G. Bluemn, I.M. Coleman, J.M. Lucas, R.T. Coleman, S. Hernandez-Lopez, R. Tharakan, D. Bianchi-Frias, R.F. Dumpit, A. Kaipainen, A.N. Corella, Y.C. Yang, M.D. Nyquist, E. Mostaghel, A.C. Hsieh, X. Zhang, E. Corey, L.G. Brown, H.M. Nguyen, K. Pienta, M. Ittmann, M. Schweizer, L.D. True, D. Wise, P.S. Rennie, R.L. Vessella, C. Morrissey, P.S. Nelson, Cancer Cell 32, 474-489 e476 (2017). https://doi.org/10.1016/j.ccell.2017.09.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. V. Conteduca, C. Oromendia, K.W. Eng, R. Bareja, M. Sigouros, A. Molina, B.M. Faltas, A. Sboner, J.M. Mosquera, O. Elemento, D.M. Nanus, S.T. Tagawa, K.V. Ballman, H. Beltran, Eur. J. Cancer 121, 7–18 (2019). https://doi.org/10.1016/j.ejca.2019.08.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. H. Beltran, D.S. Rickman, K. Park, S.S. Chae, A. Sboner, T.Y. MacDonald, Y. Wang, K.L. Sheikh, S. Terry, S.T. Tagawa, R. Dhir, J.B. Nelson, A. de la Taille, Y. Allory, M.B. Gerstein, S. Perner, K.J. Pienta, A.M. Chinnaiyan, Y. Wang, C.C. Collins, M.E. Gleave, F. Demichelis, D.M. Nanus, M.A. Rubin, Cancer Discov. 1, 487–495 (2011). https://doi.org/10.1158/2159-8290.CD-11-0130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. H.-L. Tan, A. Sood, H.A. Rahimi, W. Wang, N. Gupta, J. Hicks, S. Mosier, C.D. Gocke, J.I. Epstein, G.J. Netto, W. Liu, W.B. Isaacs, A.M. De Marzo, T.L. Lotan, Clin. Cancer Res. 20, 890–903 (2014). https://doi.org/10.1158/1078-0432.CCR-13-1982

    Article  CAS  PubMed  Google Scholar 

  7. M.D. Nyquist, A. Corella, I. Coleman, N. De Sarkar, A. Kaipainen, G. Ha, R. Gulati, L. Ang, P. Chatterjee, J. Lucas, C. Pritchard, G. Risbridger, J. Isaacs, B. Montgomery, C. Morrissey, E. Corey, P.S. Nelson, Cell Rep. 31, 107669 (2020). https://doi.org/10.1016/j.celrep.2020.107669

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. S.Y. Ku, S. Rosario, Y. Wang, P. Mu, M. Seshadri, Z.W. Goodrich, M.M. Goodrich, D.P. Labbe, E.C. Gomez, J. Wang, H.W. Long, B. Xu, M. Brown, M. Loda, C.L. Sawyers, L. Ellis, D.W. Goodrich, Science 355, 78–83 (2017). https://doi.org/10.1126/science.aah4199

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. S. Deng, C. Wang, Y. Wang, Y. Xu, X. Li, N.A. Johnson, A. Mukherji, U.G. Lo, L. Xu, J. Gonzalez, L.A. Metang, J. Ye, C.R. Tirado, K. Rodarte, Y. Zhou, Z. Xie, C. Arana, V. Annamalai, X. Liu, D.J. Vander Griend, D. Strand, J.T. Hsieh, B. Li, G. Raj, T. Wang, P. Mu, Nat. Cancer 3, 1071–1087 (2022). https://doi.org/10.1038/s43018-022-00431-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. A. Schroeder, A. Herrmann, G. Cherryholmes, C. Kowolik, R. Buettner, S. Pal, H. Yu, G. Muller-Newen, R. Jove, Cancer Res. 74, 1227–1237 (2014). https://doi.org/10.1158/0008-5472.CAN-13-0594

    Article  CAS  PubMed  Google Scholar 

  11. M. Rokavec, M.G. Oner, H. Li, R. Jackstadt, L. Jiang, D. Lodygin, M. Kaller, D. Horst, P.K. Ziegler, S. Schwitalla, J. Slotta-Huspenina, F.G. Bader, F.R. Greten, H. Hermeking, J. Clin. Invest. 124, 1853–1867 (2014). https://doi.org/10.1172/JCI73531

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. G. Canesin, V. Maggio, M. Palominos, A. Stiehm, H.R. Contreras, E.A. Castellon, J. Morote, R. Paciucci, N.J. Maitland, A. Bjartell, R. Hellsten, Sci. Rep. 10, 13958 (2020). https://doi.org/10.1038/s41598-020-70948-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. J. Luo, K. Wang, S. Yeh, Y. Sun, L. Liang, Y. Xiao, W. Xu, Y. Niu, L. Cheng, S.N. Maity, R. Jiang, C. Chang, Nat. Commun. 10, 2571 (2019). https://doi.org/10.1038/s41467-019-09784-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. A. Rojas, G. Liu, I. Coleman, P.S. Nelson, M. Zhang, R. Dash, P.B. Fisher, S.R. Plymate, J.D. Wu, Oncogene 30, 2345–2355 (2011). https://doi.org/10.1038/onc.2010.605

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. C. Enriquez, V. Cancila, R. Ferri, R. Sulsenti, I. Fischetti, M. Milani, P. Ostano, I. Gregnanin, M. Mello-Grand, E. Berrino, M. Bregni, G. Renne, C. Tripodo, M.P. Colombo, E. Jachetti, Cancer Res. (2021). https://doi.org/10.1158/0008-5472.CAN-21-0163

    Article  PubMed  PubMed Central  Google Scholar 

  16. J.K. Lee, J.W. Phillips, B.A. Smith, J.W. Park, T. Stoyanova, E.F. McCaffrey, R. Baertsch, A. Sokolov, J.G. Meyerowitz, C. Mathis, D. Cheng, J.M. Stuart, K.M. Shokat, W.C. Gustafson, J. Huang, O.N. Witte, Cancer Cell 29, 536–547 (2016). https://doi.org/10.1016/j.ccell.2016.03.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. A. Davies, S. Nouruzi, D. Ganguli, T. Namekawa, D. Thaper, S. Linder, F. Karaoglanoglu, M.E. Omur, S. Kim, M. Kobelev, S. Kumar, O. Sivak, C. Bostock, J. Bishop, M. Hoogstraat, A. Talal, S. Stelloo, H. van der Poel, A.M. Bergman, M. Ahmed, L. Fazli, H. Huang, W. Tilley, D. Goodrich, F.Y. Feng, M. Gleave, H.H. He, F. Hach, W. Zwart, H. Beltran, L. Selth, A. Zoubeidi, Nat. Cell Biol. 23, 1023–1034 (2021). https://doi.org/10.1038/s41556-021-00743-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. S. Nouruzi, D. Ganguli, N. Tabrizian, M. Kobelev, O. Sivak, T. Namekawa, D. Thaper, S.C. Baca, M.L. Freedman, A. Aguda, A. Davies, A. Zoubeidi, Nat. Commun. 13, 2282 (2022). https://doi.org/10.1038/s41467-022-29963-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. P. Mu, Z. Zhang, M. Benelli, W.R. Karthaus, E. Hoover, C.C. Chen, J. Wongvipat, S.Y. Ku, D. Gao, Z. Cao, N. Shah, E.J. Adams, W. Abida, P.A. Watson, D. Prandi, C.H. Huang, E. de Stanchina, S.W. Lowe, L. Ellis, H. Beltran, M.A. Rubin, D.W. Goodrich, F. Demichelis, C.L. Sawyers, Science 355, 84–88 (2017). https://doi.org/10.1126/science.aah4307

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. A. Berger, N.J. Brady, R. Bareja, B. Robinson, V. Conteduca, M.A. Augello, L. Puca, A. Ahmed, E. Dardenne, X. Lu, I. Hwang, A.M. Bagadion, A. Sboner, O. Elemento, J. Paik, J. Yu, C.E. Barbieri, N. Dephoure, H. Beltran, D.S. Rickman, J. Clin. Invest. 130, 3924–3940 (2019). https://doi.org/10.1172/JCI127961

    Article  Google Scholar 

  21. N. Spetsieris, M. Boukovala, G. Patsakis, I. Alafis and E. Efstathiou, Cancers (Basel). 12(12), 3792 (2020). https://doi.org/10.3390/cancers12123792

  22. H. Beltran, C. Oromendia, D.C. Danila, B. Montgomery, C. Hoimes, R.Z. Szmulewitz, U. Vaishampayan, A.J. Armstrong, M. Stein, J. Pinski, J.M. Mosquera, V. Sailer, R. Bareja, A. Romanel, N. Gumpeni, A. Sboner, E. Dardenne, L. Puca, D. Prandi, M.A. Rubin, H.I. Scher, D.S. Rickman, F. Demichelis, D.M. Nanus, K.V. Ballman, S.T. Tagawa, Clin. Cancer Res 25, 43–51 (2019). https://doi.org/10.1158/1078-0432.CCR-18-1912

    Article  CAS  PubMed  Google Scholar 

  23. A.S. Mansfield, D.S. Hong, C.L. Hann, A.F. Farago, H. Beltran, S.N. Waqar, A.E. Hendifar, L.B. Anthony, M.H. Taylor, A.H. Bryce, S.T. Tagawa, K. Lewis, J. Niu, C.H. Chung, J.M. Cleary, M. Rossi, C. Ludwig, R. Valenzuela, Y. Luo, R. Aggarwal, N.P.J. Precis, Oncol 5, 74 (2021). https://doi.org/10.1038/s41698-021-00214-y

    Article  CAS  Google Scholar 

  24. L.C. Brown, S. Halabi, J.A. Somarelli, M. Humeniuk, Y. Wu, T. Oyekunle, L. Howard, J. Huang, M. Anand, C. Davies, P. Patel, J. Staats, K.J. Weinhold, M.R. Harrison, T. Zhang, D.J. George, A.J. Armstrong, Prostate Cancer Prostatic. Dis. (2022). https://doi.org/10.1038/s41391-022-00524-7

    Article  PubMed  PubMed Central  Google Scholar 

  25. J. Drost, W.R. Karthaus, D. Gao, E. Driehuis, C.L. Sawyers, Y. Chen, H. Clevers, Nat. Protoc. 11, 347–358 (2016). https://doi.org/10.1038/nprot.2016.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. E. Dardenne, H. Beltran, M. Benelli, K. Gayvert, A. Berger, L. Puca, J. Cyrta, A. Sboner, Z. Noorzad, T. MacDonald, C. Cheung, K.S. Yuen, D. Gao, Y. Chen, M. Eilers, J.M. Mosquera, B.D. Robinson, O. Elemento, M.A. Rubin, F. Demichelis, D.S. Rickman, Cancer Cell 30, 563–577 (2016). https://doi.org/10.1016/j.ccell.2016.09.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. H. Guo, X. Ci, M. Ahmed, J.T. Hua, F. Soares, D. Lin, L. Puca, A. Vosoughi, H. Xue, E. Li, P. Su, S. Chen, T. Nguyen, Y. Liang, Y. Zhang, X. Xu, J. Xu, A.V. Sheahan, W. Ba-Alawi, S. Zhang, O. Mahamud, R.N. Vellanki, M. Gleave, R.G. Bristow, B. Haibe-Kains, J.T. Poirier, C.M. Rudin, M.S. Tsao, B.G. Wouters, L. Fazli, F.Y. Feng, L. Ellis, T. van der Kwast, A. Berlin, M. Koritzinsky, P.C. Boutros, A. Zoubeidi, H. Beltran, Y. Wang, H.H. He, Nat. Commun. 10, 278 (2019). https://doi.org/10.1038/s41467-018-08133-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. P. Mu, Z.D. Zhang, M. Benelli, W.R. Karthaus, E. Hoover, C.C. Chen, J. Wongvipat, S.Y. Ku, D. Gao, Z. Cao, N. Shah, E.J. Adams, W. Abida, P.A. Watson, D. Prandi, C.H. Huang, E. de Stanchina, S.W. Lowe, L. Ellis, H. Beltran, M.A. Rubin, D.W. Goodrich, F. Demichelis, C.L. Sawyers, Science 355, 84–88 (2017). https://doi.org/10.1126/science.aah4307

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. A. Davies, S. Nouruzi, D. Ganguli, T. Namekawa, D. Thaper, S. Linder, F. Karaoğlanoğlu, M.E. Omur, S. Kim, M. Kobelev, S. Kumar, O. Sivak, C. Bostock, J. Bishop, M. Hoogstraat, A. Talal, S. Stelloo, H. Van Der Poel, A.M. Bergman, M. Ahmed, L. Fazli, H. Huang, W. Tilley, D. Goodrich, F.Y. Feng, M. Gleave, H.H. He, F. Hach, W. Zwart, H. Beltran, L. Selth, A. Zoubeidi, Nature Cell Biol. 23, 1023–1034 (2021). https://doi.org/10.1038/s41556-021-00743-5

    Article  CAS  PubMed  Google Scholar 

  30. C. Bimbi, V.M. Riccardi, D. Koumoundourou, G. Kyriakou, Dermatol. Ther. 33, e13670 (2020). https://doi.org/10.1111/dth.13670

    Article  PubMed  Google Scholar 

  31. F.M. Khan, E. Saleh, H. Alawadhi, R. Harati, W.-H. Zimmermann, R. El-Awady, Cancer Biol. Ther. 19, 25–33 (2018). https://doi.org/10.1080/15384047.2017.1394544

    Article  CAS  PubMed  Google Scholar 

  32. M. Groeger, G. Spanier, M. Wolf, J. Deschner, P. Proff, A. Schroder, C. Kirschneck, Plos One 15, e0237040 (2020). https://doi.org/10.1371/journal.pone.0237040

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. C.L. Lee, S.H. Hsu, Y.J. Jong, C.H. Hung, J.L. Suen, Int. Arch. Allergy Immunol. 160, 265–274 (2013). https://doi.org/10.1159/000341637

    Article  CAS  PubMed  Google Scholar 

  34. N.A. El-Shitany, K. El-Desoky, Drug Des. Devel. Ther. 9, 5237–5246 (2015). https://doi.org/10.2147/DDDT.S88337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Z. Chen, H. Sun, J. Wang, L. Ni, X. Gu, S. Ge, Q. Chen, L. Mu, X. Cheng, Endocr. J. 64, 411–416 (2017). https://doi.org/10.1507/endocrj.EJ16-0458

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

The work was supported by National Natural Science Foundation of China (No 82072847, 81772742, 82172868, 81972578), Ren Ji Hospital (PYI20-04, LYZXHXKT220845, 2020LYRJ-002, PNO-0106, RJKY18-02). The funders had no role in study design, data collection and analysis, decision to publish, or manuscript preparation.

Author information

Author notes

  1. Yiyi Ji, Bo Liu and Lei Chen contributed equally to this work and share first authorship.

Authors and Affiliations

  1. Department of Urology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200120, China

    Yiyi Ji, Bo Liu, Lei Chen, Ang Li, Kai Shen, Ruopeng Su, Weiwei Zhang, Yinjie Zhu, Qi Wang & Wei Xue

  2. Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200120, China

    Qi Wang

Authors
  1. Yiyi Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bo Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lei Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kai Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ruopeng Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Weiwei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yinjie Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Qi Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Wei Xue
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

QW, and WX contributed to conception and design of the study. YJ, BL, and LC organized the database. YJ, RS, and KS performed the statistical analysis. YJ, BL, and LC wrote the first draft of the manuscript. AL and WZ wrote sections of the manuscript. QW, YZ, and WX obtained the funding. All authors contributed to manuscript revision, read, and approved the submitted version.

Corresponding authors

Correspondence to Yinjie Zhu, Qi Wang or Wei Xue.

Ethics declarations

Ethics approval

All mice experimental procedures were approved by the Research Ethics Committee of Ren Ji Hospital. The research was conducted in accordance with the Ethical Principles of Measures for Ethical Review of Biomedical Research Involving Human Beings and the Declaration of Helsinki.

Competing interests

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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.

Supplementary file1 (DOCX 632 KB)

Supplementary file2 (PDF 6832 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

Ji, Y., Liu, B., Chen, L. et al. Repurposing ketotifen as a therapeutic strategy for neuroendocrine prostate cancer by targeting the IL-6/STAT3 pathway. Cell Oncol. 46, 1445–1456 (2023). https://doi.org/10.1007/s13402-023-00822-9

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13402-023-00822-9

Keywords

Search

Navigation