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:

TNF-α-induced down-regulation of type I interferon receptor contributes to acquired resistance of cervical squamous cancer to Cisplatin

The Journal of Antibiotics volume 77, pages 102–110 (2024)Cite this article

Subjects

Abstract

We aimed to investigate the effects of tumor necrosis factor (TNF)-α on the expression of interferon α/β receptor subunit 1 (IFNAR1) and cervical squamous cancer (CSCC) resistance to Cisplatin, as well as the underlying mechanisms. Kaplan–Meier analysis was used to plot the overall survival curves. SiHa cells were treated with 20 ng/ml TNF-α to determine cell proliferation in human CSCC cells and the expression of IFNAR1. The effects of TNF-α on the downstream signaling pathway, including casein kinase 1α (CK1α), were investigated using the caspase protease inhibitor FK009, the c-Jun kinase inhibitor SP600125, and the nuclear factor kappa-B inhibitor ammonium pyrrolidinedithiocarbamate (PDTC). TNF-α induced down-regulation of IFNAR1 in human CSCC cells and promoted proliferation of SiHa cells. SiHa cells were transfected with the catalytic inactive mutant CK1α K49A, and the ability of TNF-α to induce down-regulation of IFNAR1 expression was found to be significantly diminished in this context. FK009 and PDTC had no obvious effect on the expression of CK1α, however, SP600125 significantly reduced the expression of CK1α in the presence of TNF-α. SiHa cells treated with TNF-α showed reduced sensitivity to Cisplatin and exhibited higher cell viability, while the sensitivity of SiHa cells to Cisplatin was restored after treatment with CK1α inhibitor D4476. Additionally, we constructed a TNF-α overexpressing SiHa cell line and a transplanted tumor model. The results were similar to those of in vitro efficacy. We demonstrate that TNF-α-induced down-regulation of type I interferon receptor contributes to acquired resistance of cervical squamous cancer to Cisplatin.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

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

Similar content being viewed by others

Data availability

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

References

  1. Dai J, Pan Y, Chen Y, Yao S. A panel of seven immune-related genes can serve as a good predictive biomarker for cervical squamous cell carcinoma. Front Genet. 2022;13:1024508.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Chen P, Jiao L, Ren F, Wang DB. Clinical value of serum squamous cell carcinoma antigen levels in predicting chemosensitivity, lymph node metastasis, and prognosis in patients with cervical squamous cell carcinoma. BMC Cancer. 2020;20:423.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Xie N, et al. Tumor budding correlates with occult cervical lymph node metastasis and poor prognosis in clinical early-stage tongue squamous cell carcinoma. J Oral Pathol Med. 2015;44:266–72.

    Article  PubMed  Google Scholar 

  4. Gliniewicz A, Zielinska A, Kwiatkowska K, Dudek-Godeau D, Bielska-Lasota M. Survival in women diagnosed with breast and cervical cancer in Poland–compared to European countries, based on CONCORD - 3 Programme. Przegl Epidemiol. 2018;72:499–508.

    PubMed  Google Scholar 

  5. Gomez-Vargas V, et al. Screening history and survival among women with cervical cancer in Puerto Rico. J Low Genit Tract Dis. 2023;27:19–23.

    Article  PubMed  Google Scholar 

  6. Martin-Hirsch P, et al. Survival of women with early-stage cervical cancer in the UK treated with minimal access and open surgery. BJOG. 2019;126:956–9.

    Article  CAS  PubMed  Google Scholar 

  7. Budhwani M, Mazzieri R, Dolcetti R. Plasticity of type I interferon-mediated responses in cancer therapy: from anti-tumor immunity to resistance. Front Oncol. 2018;8:322.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Greten FR, Grivennikov SI. Inflammation and cancer: triggers, mechanisms, and consequences. Immunity. 2019;51:27–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Cheon H, Borden EC, Stark GR. Interferons and their stimulated genes in the tumor microenvironment. Semin Oncol. 2014;41:156–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Thomas G, et al. Intra-tumoral activation of endosomal TLR pathways reveals a distinct role for TLR3 agonist dependent type-1 interferons in shaping the tumor immune microenvironment. Front Oncol. 2021;11:711673.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Minn AJ. Interferons and the immunogenic effects of cancer therapy. Trends Immunol. 2015;36:725–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Enomoto H, et al. The in vivo antitumor effects of type I-interferon against hepatocellular carcinoma: the suppression of tumor cell growth and angiogenesis. Sci Rep. 2017;7:12189.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Zhao Q, et al. 10,11-dehydrocurvularin exerts antitumor effect against human breast cancer by suppressing STAT3 activation. Acta Pharmacol Sin. 2021;42:791–800.

    Article  CAS  PubMed  Google Scholar 

  14. Kumar KG, Krolewski JJ, Fuchs SY. Phosphorylation and specific ubiquitin acceptor sites are required for ubiquitination and degradation of the IFNAR1 subunit of type I interferon receptor. J Biol Chem. 2004;279:46614–20.

    Article  CAS  PubMed  Google Scholar 

  15. Zheng H, et al. Vascular endothelial growth factor-induced elimination of the type 1 interferon receptor is required for efficient angiogenesis. Blood. 2011;118:4003–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bartoli M, et al. Vascular endothelial growth factor activates STAT proteins in aortic endothelial cells. J Biol Chem. 2000;275:33189–92.

    Article  CAS  PubMed  Google Scholar 

  17. Ahmed MI, Salahy EE, Fayed ST, El-Hefnawy NG, Khalifa A. Human papillomavirus infection among Egyptian females with cervical carcinoma: relationship to spontaneous apoptosis and TNF-alpha. Clin Biochem. 2001;34:491–8.

    Article  CAS  PubMed  Google Scholar 

  18. Liu J, et al. Mammalian casein kinase 1alpha and its leishmanial ortholog regulate stability of IFNAR1 and type I interferon signaling. Mol Cell Biol. 2009;29:6401–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Xia C, et al. Casein kinase 1alpha mediates the degradation of receptors for type I and type II interferons caused by hemagglutinin of influenza a virus. J Virol. 2018;92:e00006–18.

  20. Rice TW, et al. Recommendations for pathologic staging (pTNM) of cancer of the esophagus and esophagogastric junction for the 8th edition AJCC/UICC staging manuals. Dis Esophagus. 2016;29:897–905.

    Article  CAS  PubMed  Google Scholar 

  21. Huangfu WC, et al. Inflammatory signaling compromises cell responses to interferon alpha. Oncogene. 2012;31:161–72.

    Article  CAS  PubMed  Google Scholar 

  22. Andzinski L, et al. Type I IFNs induce anti-tumor polarization of tumor associated neutrophils in mice and human. Int J Cancer. 2016;138:1982–93.

    Article  CAS  PubMed  Google Scholar 

  23. Liao J, et al. Type I IFNs repolarized a CD169(+) macrophage population with anti-tumor potentials in hepatocellular carcinoma. Mol Ther. 2022;30:632–43.

    Article  CAS  PubMed  Google Scholar 

  24. Sangfelt O, et al. Induction of apoptosis and inhibition of cell growth are independent responses to interferon-alpha in hematopoietic cell lines. Cell Growth Differ. 1997;8:343–52.

    CAS  PubMed  Google Scholar 

  25. Zhen S, Lu J, Liu YH, Chen W, Li X. Synergistic antitumor effect on cervical cancer by rational combination of PD1 blockade and CRISPR-Cas9-mediated HPV knockout. Cancer Gene Ther. 2020;27:168–78.

    Article  CAS  PubMed  Google Scholar 

  26. Street D, et al. Interferon-gamma enhances susceptibility of cervical cancer cells to lysis by tumor-specific cytotoxic T cells. Gynecol Oncol. 1997;65:265–72.

    Article  CAS  PubMed  Google Scholar 

  27. Kim EY, Moudgil KD. Regulation of autoimmune inflammation by pro-inflammatory cytokines. Immunol Lett. 2008;120:1–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. de Matos LG, et al. Association between Toll-like receptor and tumor necrosis factor immunological pathways in uterine cervical neoplasms. Tumori. 2017;103:81–6.

    Article  PubMed  Google Scholar 

  29. Ma D, et al. KLF5 promotes cervical cancer proliferation, migration and invasion in a manner partly dependent on TNFRSF11a expression. Sci Rep. 2017;7:15683.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Bai D, Ueno L, Vogt PK. Akt-mediated regulation of NFkappaB and the essentialness of NFkappaB for the oncogenicity of PI3K and Akt. Int J Cancer. 2009;125:2863–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hu X, Li J, Fu M, Zhao X, Wang W. The JAK/STAT signaling pathway: from bench to clinic. Signal Transduct Target Ther. 2021;6:402.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Fulcher LJ, Sapkota GP. Functions and regulation of the serine/threonine protein kinase CK1 family: moving beyond promiscuity. Biochem J. 2020;477:4603–21.

    Article  CAS  PubMed  Google Scholar 

  33. Zhang W, et al. Inhibition of LDHA suppresses cell proliferation and increases mitochondrial apoptosis via the JNK signaling pathway in cervical cancer cells. Oncol Rep. 2022;47. https://doi.org/10.3892/or.2022.8288.

  34. Yin Y, et al. JNK/AP-1 pathway is involved in tumor necrosis factor-alpha induced expression of vascular endothelial growth factor in MCF7 cells. Biomed Pharmacother. 2009;63:429–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Yang Z, Shi G, Guo J, Zhou Y, Jia J. JNK signaling pathway mediates fluoride-induced upregulation of CK1alpha during enamel formation. Caries Res. 2021;55:225–33.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Gynecology, Zibo Central Hospital, No. 54 Gongqingtuan West Road, Zibo, 255036, Shandong, China

    Yani Yu, Jia Yu, Xiaorong Cui, Xin Sun & Xiaohui Yu

Authors
  1. Yani Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jia Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiaorong Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xin Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiaohui Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jia Yu.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

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

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

Yu, Y., Yu, J., Cui, X. et al. TNF-α-induced down-regulation of type I interferon receptor contributes to acquired resistance of cervical squamous cancer to Cisplatin. J Antibiot 77, 102–110 (2024). https://doi.org/10.1038/s41429-023-00686-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41429-023-00686-z

Search

Advanced search

Quick links