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.

  • Brief Communication
  • Published:

Blocking the functional domain of cancer cell surface TIP1 upregulates Midkine via the β-catenin/Wnt signaling pathway

Cancer Gene Therapy volume 32, pages 785–792 (2025)Cite this article

Subjects

Abstract

Drug resistance exhibited by cancer cells remains one of the primary reasons for the failure of therapeutic approaches to increase the survival of cancer patients. Marginal improvement in therapeutic efficacy with current treatment approaches for non-small cell lung cancer (NSCLC) mandates new treatment strategies. Tax interacting Protein-1 (TIP1) is a radiation-inducible molecular target involved in various cancer pathways. TIP1 expression correlates with poor survival in NSCLC patients. Antibody blocking the functional domain of TIP1 reduced cell proliferation and sensitized cancer cells to radiation. A ten-fold increase in Midkine (MDK) was observed in the proteomic analysis of cells treated with anti-TIP1 antibody. Wnt signaling activation led to MDK upregulation at the mRNA and protein levels following TIP1 blockade. Genetic silencing of β-catenin abrogated the induction of MDK following anti-TIP1 antibody treatment. Inhibiting TIP1 along with MDK showed a reduction in the colony-forming capability of the cells, indicating that MDK upregulation might be a strategy employed by cancer cells to combat the anti-proliferative capabilities of the anti-TIP1 antibody. Co-targeting cell surface TIP1 and MDK may be an effective therapeutic strategy for NSCLC patients.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Fig. 1: Midkine is upregulated following TIP1 blockade.
Fig. 2: TIP1 interacts with β-catenin in NSCLC cells.
Fig. 3: β-catenin translocates to the nucleus, and Wnt signaling is activated following blocking of the TIP1 functional domain.
Fig. 4: Knockdown of β-catenin abrogates upregulation of Midkine following blockade of the functional domain of TIP1.

Similar content being viewed by others

References

  1. Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin. 2024;74:12–49.

    Article  PubMed  Google Scholar 

  2. Chan BA, Hughes BG. Targeted therapy for non-small cell lung cancer: current standards and the promise of the future. Transl Lung Cancer Res. 2015;4:36–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Rivera-Concepcion J, Uprety D, Adjei AA. Challenges in the use of targeted therapies in non-small cell lung cancer. Cancer Res Treat. 2022;54:315–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Vander Velde R, Yoon N, Marusyk V, Durmaz A, Dhawan A, Miroshnychenko D, et al. Resistance to targeted therapies as a multifactorial, gradual adaptation to inhibitor specific selective pressures. Nat Commun. 2020;11:2393.

    Article  Google Scholar 

  5. Mohanty S, Ovee M, Banerjee M. PDZ domain recognition: Insight from Human Tax-Interacting Protein 1 (TIP-1) interaction with target proteins. Biology. 2015;4:88–103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Yan H, Kapoor V, Nguyen K, Akers WJ, Li H, Scott J, et al. Anti-tax interacting protein-1 (TIP-1) monoclonal antibody targets human cancers. Oncotarget. 2016;7:43352–62.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Kapoor V, Singh AK, Rogers BE, Thotala D, Hallahan DE. PEGylated peptide to TIP1 is a novel targeting agent that binds specifically to various cancers in vivo. J Control Rel. 2019;298:194–201.

    Article  CAS  Google Scholar 

  8. Lewis CD, Singh AK, Hsu FF, Thotala D, Hallahan DE, Kapoor V. Targeting a radiosensitizing antibody-drug conjugate to a radiation-inducible antigen. Clin Cancer Res. 2021;27:3224–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Johnson M, Sharma M, Jamieson C, Henderson JM, Mok MT, Bendall L, et al. Regulation of beta-catenin trafficking to the membrane in living cells. Cell Signal. 2009;21:339–48.

    Article  CAS  PubMed  Google Scholar 

  10. Kim WK, Kwon Y, Jang M, Park M, Kim J, Cho S, et al. beta-catenin activation down-regulates cell-cell junction-related genes and induces epithelial-to-mesenchymal transition in colorectal cancers. Sci Rep. 2019;9:18440.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Shah K, Kazi JU. Phosphorylation-dependent regulation of WNT/Beta-Catenin Signaling. Front Oncol. 2022;12:858782.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Liu J, Xiao Q, Xiao J, Niu C, Li Y, Zhang X, et al. Wnt/beta-catenin signalling: function, biological mechanisms, and therapeutic opportunities. Signal Transduct Target Ther. 2022;7:3.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Singh AK, Dadey DY, Rau MJ, Fitzpatrick J, Shah HK, Saikia M, et al. Blocking the functional domain of TIP1 by antibodies sensitizes cancer to radiation therapy. Biomed Pharmacother. 2023;166:115341.

    Article  CAS  PubMed  Google Scholar 

  14. Saikia M, Cheung N, Singh AK, Kapoor V. Role of Midkine in cancer drug resistance: regulators of its expression and its molecular targeting. Int J Mol Sci 2023;24:8739.

  15. Cerezo-Wallis D, Contreras-Alcalde M, Troule K, Catena X, Mucientes C, Calvo TG, et al. Midkine rewires the melanoma microenvironment toward a tolerogenic and immune-resistant state. Nat Med. 2020;26:1865–77.

    Article  CAS  PubMed  Google Scholar 

  16. Ding L, Wang N, Wang Q, Fan X, Xin Y, Wang S. Midkine inhibition enhances anti-PD-1 immunotherapy in sorafenib-treated hepatocellular carcinoma via preventing immunosuppressive MDSCs infiltration. Cell Death Discov. 2023;9:92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Huang WL, Hsu YC, Luo CW, Chang SJ, Hung YH, Lai CY, et al. Targeting the CDK7-MDK axis to suppresses irinotecan resistance in colorectal cancer. Life Sci 2024:122914.

  18. Singh AK, Lewis CD, Boas C, Diebolder P, Jethva PN, Rhee A, et al. Development of a [89Zr]Zr-labeled human antibody using a novel phage-displayed human scFv Library. Clin Cancer Res. 2024;30:1293–306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Nabbi A, Riabowol K. Rapid isolation of nuclei from cells in vitro. Cold Spring Harb Protoc. 2015;2015:769–72.

    Article  PubMed  Google Scholar 

  20. Stewart DJ. Wnt signaling pathway in non-small cell lung cancer. J Natl Cancer Inst. 2014;106:djt356.

    Article  PubMed  Google Scholar 

  21. Muto S, Enta A, Maruya Y, Inomata S, Yamaguchi H, Mine H, et al. Wnt/beta-Catenin signaling and resistance to immune checkpoint inhibitors: from non-small-cell lung cancer to other cancers. Biomedicines 2023;11:190.

  22. Kanamori M, Sandy P, Marzinotto S, Benetti R, Kai C, Hayashizaki Y, et al. The PDZ protein tax-interacting protein-1 inhibits beta-catenin transcriptional activity and growth of colorectal cancer cells. J Biol Chem. 2003;278:38758–64.

    Article  CAS  PubMed  Google Scholar 

  23. Zhang J, Yan X, Shi C, Yang X, Guo Y, Tian C, et al. Structural basis of beta-catenin recognition by Tax-interacting protein-1. J Mol Biol. 2008;384:255–63.

    Article  CAS  PubMed  Google Scholar 

  24. Persad A, Venkateswaran G, Hao L, Garcia ME, Yoon J, Sidhu J, et al. Active beta-catenin is regulated by the PTEN/PI3 kinase pathway: a role for protein phosphatase PP2A. Genes Cancer. 2016;7:368–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Staal FJ, van Noort M, Strous GJ, Clevers HC. Wnt signals are transmitted through N-terminally dephosphorylated beta-catenin. EMBO Rep. 2002;3:63–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zhang YK, Huang ZJ, Liu S, Liu YP, Song AA, Song XJ. WNT signaling underlies the pathogenesis of neuropathic pain in rodents. J Clin Invest. 2013;123:2268–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Vuong LT, Mlodzik M. Wg/Wnt-signaling-induced nuclear translocation of beta-catenin is attenuated by a beta-catenin peptide through its interference with the IFT-A complex. Cell Rep. 2024;43:114362.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Xia X, Qian S, Soriano S, Wu Y, Fletcher AM, Wang XJ, et al. Loss of presenilin 1 is associated with enhanced beta-catenin signaling and skin tumorigenesis. Proc Natl Acad Sci USA. 2001;98:10863–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hao H, Maeda Y, Fukazawa T, Yamatsuji T, Takaoka M, Bao XH, et al. Inhibition of the growth factor MDK/midkine by a novel small molecule compound to treat non-small cell lung cancer. PLoS One. 2013;8:e71093.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ishida N, Fukazawa T, Maeda Y, Yamatsuji T, Kato K, Matsumoto K, et al. A novel PI3K inhibitor iMDK suppresses non-small cell lung Cancer cooperatively with A MEK inhibitor. Exp Cell Res. 2015;335:197–206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Masui M, Okui T, Shimo T, Takabatake K, Fukazawa T, Matsumoto K, et al. Novel Midkine Inhibitor iMDK inhibits tumor growth and angiogenesis in oral squamous cell carcinoma. Anticancer Res. 2016;36:2775–81.

    CAS  PubMed  Google Scholar 

  32. Ueno M, Kariya R, Gunya S, Cheevapruk K, Okada S. Midkine inhibitor (iMDK) induces apoptosis of primary effusion lymphoma via G2/M cell cycle arrest. Leuk Res. 2022;116:106826.

    Article  CAS  PubMed  Google Scholar 

  33. Kang HC, Kim IJ, Park HW, Jang SG, Ahn SA, Yoon SN, et al. Regulation of MDK expression in human cancer cells modulates sensitivities to various anticancer drugs: MDK overexpression confers to a multi-drug resistance. Cancer Lett. 2007;247:40–47.

    Article  CAS  PubMed  Google Scholar 

  34. Tang SL, Gao YL, Chen XB. Wnt/beta-catenin up-regulates Midkine expression in glioma cells. Int J Clin Exp Med. 2015;8:12644–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Shi Y, Ge J, Li R, Li Y, Lin L. Targeting of Midkine alleviates cardiac hypertrophy via attenuation of oxidative stress and autophagy. Peptides. 2022;153:170800.

    Article  CAS  PubMed  Google Scholar 

  36. Shin DH, Jo JY, Kim SH, Choi M, Han C, Choi BK, et al. Midkine is a potential therapeutic target of tumorigenesis, angiogenesis, and metastasis in non-small cell lung cancer. Cancers (Basel). 2020;12:2402.

  37. Sueyoshi T, Jono H, Shinriki S, Ota K, Ota T, Tasaki M, et al. Therapeutic approaches targeting Midkine suppress tumor growth and lung metastasis in osteosarcoma. Cancer Lett. 2012;316:23–30.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Nathan Cheung and Kristina Dalton for their assistance in the experiments. We thank Reid R Townsend and Petra Gilmore at the Washington University Proteomics Core for quantitative proteomics analysis. We also thank the Siteman Cancer Center’s shared research facilities and the Elizabeth & James McDonnell Endowment for DH.

Funding

This study was supported by the Lung Cancer Research Foundation (Vaishali Kapoor) and K22CA234404 (Vaishali Kapoor).

Author information

Authors and Affiliations

  1. Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA

    Minakshi Saikia, Harendra Kumar Shah, Dennis E. Hallahan, Abhay Kumar Singh & Vaishali Kapoor

  2. Siteman Cancer Center, St. Louis, MO, USA

    Dennis E. Hallahan & Vaishali Kapoor

Authors
  1. Minakshi Saikia
    View author publications

    Search author on:PubMed Google Scholar

  2. Harendra Kumar Shah
    View author publications

    Search author on:PubMed Google Scholar

  3. Dennis E. Hallahan
    View author publications

    Search author on:PubMed Google Scholar

  4. Abhay Kumar Singh
    View author publications

    Search author on:PubMed Google Scholar

  5. Vaishali Kapoor
    View author publications

    Search author on:PubMed Google Scholar

Contributions

MS performed the investigation, analysis, and wrote the manuscript. HKS performed the investigation and analysis. DEH reviewed and edited the manuscript. AKS performed the investigation, analysis, wrote, and reviewed the manuscript. VK conceptualized, supervised, and provided funding for the study, performed investigation and analysis, and wrote and edited the manuscript. All the authors reviewed and approved the manuscript.

Corresponding authors

Correspondence to Abhay Kumar Singh or Vaishali Kapoor.

Ethics declarations

Competing interests

Dr. Hallahan is a founder and shareholder of Medical Guidance Systems LLC, which is developing human anti-TIP1 antibodies. Vaishali Kapoor and Abhay Kumar Singh are inventors on pending patents. Other authors state that there are no conflicts of interest. All authors agree to send an individual conflict of interest form if requested by the journal.

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

Saikia, M., Shah, H.K., Hallahan, D.E. et al. Blocking the functional domain of cancer cell surface TIP1 upregulates Midkine via the β-catenin/Wnt signaling pathway. Cancer Gene Ther 32, 785–792 (2025). https://doi.org/10.1038/s41417-025-00922-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41417-025-00922-8

Search

Advanced search

Quick links