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:

Systems analysis identifies endothelin 1 axis blockade for enhancing the anti-tumor effect of multikinase inhibitor

Cancer Gene Therapy volume 29, pages 845–858 (2022)Cite this article

Subjects

Abstract

Multikinase inhibitors, such as sorafenib, are used for the treatment of advanced carcinomas but the response shows limited efficacy or varies a lot with patients. Here we adopted the systems approach combined with high-throughput data analysis to discover key mechanism embedded in the drug response. When analyzing the transcriptomic data from the Cancer Cell Line Encyclopedia (CCLE) database, endothelin 1 (EDN1) was enriched in cancer cells with low responsiveness to sorafenib. We found that the level of EDN1 is higher in the tissue and blood of hepatocellular carcinoma (HCC) patients showing poor response to sorafenib. In vitro experiment showed that EDN1 not only induces activation of angiogenic-promoting pathways in HCC cells but also stimulates proliferation and migration. Moreover, EDN1 is related with poor responsiveness to sorafenib by mitigating unfolded protein response (UPR), which was validated in both transcriptomic data analysis and in silico simulation. Finally, we found that endothelin receptor B (EDNRB) antagonists can enhance the efficacy of sorafenib in both HCC cells and xenograft mouse models. Our findings provide that EDN1 is a novel diagnostic marker for sorafenib responsiveness in HCC and a basis for testing macitentan, which is currently used for pulmonary artery hypertension, in combination with sorafenib in advanced HCC patients.

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: EDN1 expression level determines different responses to sorafenib treatment.
Fig. 2: The comparison of EDN1 levels between the responder group and the non-responder group.
Fig. 3: EDN1 affects the efficacy of sorafenib and EDNRB antagonists sensitize HCC cells to sorafenib.
Fig. 4: EDN1 blunts sorafenib-induced changes in the ER stress response.
Fig. 5: Simulation of the EDN1-regulated UPR signaling network.
Fig. 6: The combination treatment with macitentan and sorafenib reduced tumor growth in vivo.

Similar content being viewed by others

Data availability

The python code for the signal flow analysis is available at https://github.com/dwgoon/sfa. All codes related to this paper may be requested from the authors. The GEO accession numbers for RNA-seq data is GSE178280.

References

  1. Garuti L, Roberti M, Bottegoni G. Multi-kinase inhibitors. Curr Med Chem. 2015;22:695–712.

    Article  CAS  PubMed  Google Scholar 

  2. Alqahtani SA, Colombo M. Multikinase inhibitors to treat hepatocellular carcinoma failures to sorafenib-time has come for a better approach. Ann Transl Med. 2020;8:1255.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Tang W, Chen Z, Zhang W, Cheng Y, Zhang B, Wu F, et al. The mechanisms of sorafenib resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects. Signal Transduct Target Ther. 2020;5:87.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Chen S, Cao Q, Wen W, Wang H. Targeted therapy for hepatocellular carcinoma: challenges and opportunities. Cancer Lett. 2019;460:1–9.

    Article  CAS  PubMed  Google Scholar 

  5. Kim HY, Lee DH, Lee JH, Cho YY, Cho EJ, Yu SJ, et al. Novel biomarker-based model for the prediction of sorafenib response and overall survival in advanced hepatocellular carcinoma: a prospective cohort study. BMC Cancer. 2018;18:307.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Voss MH, Chen D, Marker M, Hakimi AA, Lee CH, Hsieh JJ, et al. Circulating biomarkers and outcome from a randomised phase II trial of sunitinib vs everolimus for patients with metastatic renal cell carcinoma. Br J Cancer. 2016;114:642–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Tahara M, Schlumberger M, Elisei R, Habra MA, Kiyota N, Paschke R, et al. Exploratory analysis of biomarkers associated with clinical outcomes from the study of lenvatinib in differentiated cancer of the thyroid. Eur J Cancer. 2017;75:213–21.

    Article  CAS  PubMed  Google Scholar 

  8. Cervello M, McCubrey JA, Cusimano A, Lampiasi N, Azzolina A, Montalto G. Targeted therapy for hepatocellular carcinoma: novel agents on the horizon. Oncotarget. 2012;3:236–60.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–90.

    Article  CAS  PubMed  Google Scholar 

  10. Kostner AH, Sorensen M, Olesen RK, Gronbaek H, Lassen U, Ladekarl M. Sorafenib in advanced hepatocellular carcinoma: a nationwide retrospective study of efficacy and tolerability. ScientificWorldJournal. 2013;2013:931972.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Horwitz E, Stein I, Andreozzi M, Nemeth J, Shoham A, Pappo O, et al. Human and mouse VEGFA-amplified hepatocellular carcinomas are highly sensitive to sorafenib treatment. Cancer Discov. 2014;4:730–43.

    Article  CAS  PubMed  Google Scholar 

  12. Peng S, Wang Y, Peng H, Chen D, Shen S, Peng B, et al. Autocrine vascular endothelial growth factor signaling promotes cell proliferation and modulates sorafenib treatment efficacy in hepatocellular carcinoma. Hepatology. 2014;60:1264–77.

    Article  CAS  PubMed  Google Scholar 

  13. Liang Y, Zheng T, Song R, Wang J, Yin D, Wang L, et al. Hypoxia-mediated sorafenib resistance can be overcome by EF24 through Von Hippel-Lindau tumor suppressor-dependent HIF-1alpha inhibition in hepatocellular carcinoma. Hepatology. 2013;57:1847–57.

    Article  CAS  PubMed  Google Scholar 

  14. Davenport AP, Hyndman KA, Dhaun N, Southan C, Kohan DE, Pollock JS, et al. Endothelin. Pharm Rev. 2016;68:357–418.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Stow LR, Jacobs ME, Wingo CS, Cain BD. Endothelin-1 gene regulation. FASEB J. 2011;25:16–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Nelson J, Bagnato A, Battistini B, Nisen P. The endothelin axis: emerging role in cancer. Nat Rev Cancer. 2003;3:110–6.

    Article  CAS  PubMed  Google Scholar 

  17. Rosano L, Spinella F, Bagnato A. Endothelin 1 in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer. 2013;13:637–51.

    Article  CAS  PubMed  Google Scholar 

  18. Irani S, Salajegheh A, Smith RA, Lam AK. A review of the profile of endothelin axis in cancer and its management. Crit Rev Oncol Hematol. 2014;89:314–21.

    Article  PubMed  Google Scholar 

  19. Lu JW, Liao CY, Yang WY, Lin YM, Jin SL, Wang HD, et al. Overexpression of endothelin 1 triggers hepatocarcinogenesis in zebrafish and promotes cell proliferation and migration through the AKT pathway. PLoS ONE. 2014;9:e85318.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Cong N, Li Z, Shao W, Li J, Yu S. Activation of ETA receptor by endothelin-1 induces hepatocellular carcinoma cell migration and invasion via ERK1/2 and AKT signaling pathways. J Membr Biol. 2016;249:119–28.

    Article  CAS  PubMed  Google Scholar 

  21. Rosano L, Cianfrocca R, Tocci P, Spinella F, Di Castro V, Spadaro F, et al. Beta-arrestin-1 is a nuclear transcriptional regulator of endothelin-1-induced beta-catenin signaling. Oncogene. 2013;32:5066–77.

    Article  CAS  PubMed  Google Scholar 

  22. Nie S, Zhou J, Bai F, Jiang B, Chen J, Zhou J. Role of endothelin A receptor in colon cancer metastasis: in vitro and in vivo evidence. Mol Carcinog. 2014;53:E85–91.

    Article  CAS  PubMed  Google Scholar 

  23. Cianfrocca R, Rosano L, Tocci P, Sestito R, Caprara V, Di Castro V, et al. Blocking endothelin-1-receptor/beta-catenin circuit sensitizes to chemotherapy in colorectal cancer. Cell Death Differ. 2017;24:1811–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Smith MP, Rowling EJ, Miskolczi Z, Ferguson J, Spoerri L, Haass NK, et al. Targeting endothelin receptor signalling overcomes heterogeneity driven therapy failure. EMBO Mol Med. 2017;9:1011–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Won JK, Yu SJ, Hwang CY, Cho SH, Park SM, Kim K, et al. Protein disulfide isomerase inhibition synergistically enhances the efficacy of sorafenib for hepatocellular carcinoma. Hepatology. 2017;66:855–68.

    Article  CAS  PubMed  Google Scholar 

  26. Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin AA, Kim S, et al. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature. 2012;483:603–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lee D, Cho K-H. Topological estimation of signal flow in complex signaling networks. Sci Rep. 2018;8:1–11.

    Google Scholar 

  28. Lee D, Cho K-H. Signal flow control of complex signaling networks. Sci Rep. 2019;9:1–18.

    CAS  Google Scholar 

  29. Kim JR, Kim J, Kwon YK, Lee HY, Heslop-Harrison P, Cho KH. Reduction of complex signaling networks to a representative kernel. Sci Signal. 2011;4:ra35.

    Article  PubMed  Google Scholar 

  30. Liberzon A, Birger C, Thorvaldsdottir H, Ghandi M, Mesirov JP, Tamayo P. The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst. 2015;1:417–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Iurlaro R, Munoz-Pinedo C. Cell death induced by endoplasmic reticulum stress. FEBS J. 2016;283:2640–52.

    Article  CAS  PubMed  Google Scholar 

  32. Bagnato A, Rosano L. The endothelin axis in cancer. Int J Biochem Cell Biol. 2008;40:1443–51.

    Article  CAS  PubMed  Google Scholar 

  33. Carducci MA, Jimeno A. Targeting bone metastasis in prostate cancer with endothelin receptor antagonists. Clin Cancer Res. 2006;12:6296s–6300s.

    Article  CAS  PubMed  Google Scholar 

  34. Spinella F, Rosano L, Di Castro V, Decandia S, Nicotra MR, Natali PG, et al. Endothelin-1 and endothelin-3 promote invasive behavior via hypoxia-inducible factor-1alpha in human melanoma cells. Cancer Res. 2007;67:1725–34.

    Article  CAS  PubMed  Google Scholar 

  35. Rosano L, Di Castro V, Spinella F, Tortora G, Nicotra MR, Natali PG, et al. Combined targeting of endothelin A receptor and epidermal growth factor receptor in ovarian cancer shows enhanced antitumor activity. Cancer Res. 2007;67:6351–9.

    Article  CAS  PubMed  Google Scholar 

  36. Kim TH, Xiong H, Zhang Z, Ren B. beta-Catenin activates the growth factor endothelin-1 in colon cancer cells. Oncogene. 2005;24:597–604.

    Article  CAS  PubMed  Google Scholar 

  37. Rosano L, Cianfrocca R, Tocci P, Spinella F, Di Castro V, Caprara V, et al. Endothelin A receptor/beta-arrestin signaling to the Wnt pathway renders ovarian cancer cells resistant to chemotherapy. Cancer Res. 2014;74:7453–64.

    Article  CAS  PubMed  Google Scholar 

  38. Wulfing P, Kersting C, Tio J, Fischer RJ, Wulfing C, Poremba C, et al. Endothelin-1-, endothelin-A-, and endothelin-B-receptor expression is correlated with vascular endothelial growth factor expression and angiogenesis in breast cancer. Clin Cancer Res. 2004;10:2393–400.

    Article  PubMed  Google Scholar 

  39. Wang Z, Liu P, Zhou X, Wang T, Feng X, Sun YP, et al. Endothelin promotes colorectal tumorigenesis by activating YAP/TAZ. Cancer Res. 2017;77:2413–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Friemel J, Rechsteiner M, Frick L, Bohm F, Struckmann K, Egger M, et al. Intratumor heterogeneity in hepatocellular carcinoma. Clin Cancer Res. 2015;21:1951–61.

    Article  CAS  PubMed  Google Scholar 

  41. Simons M, Gordon E, Claesson-Welsh L. Mechanisms and regulation of endothelial VEGF receptor signalling. Nat Rev Mol Cell Biol. 2016;17:611–25.

    Article  CAS  PubMed  Google Scholar 

  42. Romashkova JA, Makarov SS. NF-κB is a target of AKT in anti-apoptotic PDGF signalling. Nature. 1999;401:86–90.

    Article  CAS  PubMed  Google Scholar 

  43. Cantley LC. The phosphoinositide 3-kinase pathway. Science. 2002;296:1655–7.

    Article  CAS  PubMed  Google Scholar 

  44. Di Conza G, Cafarello ST, Loroch S, Mennerich D, Deschoemaeker S, Di Matteo M, et al. The mTOR and PP2A pathways regulate PHD2 phosphorylation to fine-tune HIF1α levels and colorectal cancer cell survival under hypoxia. Cell Rep. 2017;18:1699–712.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Bruix J, Sherman M, American Association for the Study of Liver D. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53:1020–2.

    Article  PubMed  Google Scholar 

  46. European Association For The Study Of The Liver, European Organisation For Reasearch and Treatment Of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2012;56:908–43.

    Article  Google Scholar 

  47. McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM, et al. Reporting recommendations for tumor marker prognostic studies. J Clin Oncol. 2005;23:9067–72.

    Article  PubMed  Google Scholar 

  48. Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet. 2012;379:1245–55.

    Article  PubMed  Google Scholar 

  49. Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG. Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol. 2010;8:e1000412.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Heagerty PJ, Lumley T, Pepe MS. Time-dependent ROC curves for censored survival data and a diagnostic marker. Biometrics. 2000;56:337–44.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Nancy R Gough (BioSerendipity, LLC) for constructive input and editorial support. This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korea Government, the Ministry of Science and ICT (2020R1A2B5B03094920), and Electronics and Telecommunications Research Institute (ETRI) grant funded by the Korean government (21ZS1100, Core Technology Research for Self-Improving Integrated Artificial Intelligence System). It was also supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Ministry of Science & ICT (2021M3A9I4024447) and partially supported by grants from the SNUH Research Fund (number 03-2018-0390) and the Liver Research Foundation of Korea, and a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI14C1277).

Author information

Author notes

  1. These authors contributed equally: Chae Young Hwang, Su Jong Yu, Jae-Kyung Won, Sang-Min Park.

  2. These authors jointly supervised this work: Jung-Hwan Yoon, Kwang-Hyun Cho.

Authors and Affiliations

  1. Laboratory for Systems Biology and Bio-inspired Engineering, Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea

    Chae Young Hwang, Jae-Kyung Won, Sang-Min Park, Soobeom Lee & Kwang-Hyun Cho

  2. Aventi, Inc., Daejeon, Korea

    Chae Young Hwang

  3. Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea

    Su Jong Yu, Hyojin Noh, Eun Ju Cho, Jeong-Hoon Lee, Yoon Jun Kim & Jung-Hwan Yoon

  4. Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea

    Jae-Kyung Won & Kyung Bun Lee

  5. KM Data Division, Korea Institute of Oriental Medicine, Daejeon, Korea

    Sang-Min Park

  6. Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea

    Kyung-Suk Suh

Authors
  1. Chae Young Hwang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Su Jong Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jae-Kyung Won
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sang-Min Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hyojin Noh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Soobeom Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Eun Ju Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jeong-Hoon Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Kyung Bun Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yoon Jun Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kyung-Suk Suh
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jung-Hwan Yoon
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Kwang-Hyun Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

CYH, SJY, and J-KW designed and performed experiments, collected and analyzed the data, interpreted the results, and wrote the manuscript. S-MP conducted modeling, analysis, and wrote the manuscript. SL and KBL provided analytical support, and HN, EJC, and J-HL provided experimental support. YJK and K-SS contributed to the acquisition of data, analysis and interpretation of data, and material support. J-HY and K-HC designed the experiments, interpreted the results, coordinated the study, and wrote the paper. K-HC designed the project and supervised the study. All authors contributed to writing and providing feedback.

Corresponding author

Correspondence to Kwang-Hyun Cho.

Ethics declarations

Competing interests

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.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hwang, C.Y., Yu, S.J., Won, JK. et al. Systems analysis identifies endothelin 1 axis blockade for enhancing the anti-tumor effect of multikinase inhibitor. Cancer Gene Ther 29, 845–858 (2022). https://doi.org/10.1038/s41417-021-00373-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41417-021-00373-x

This article is cited by

Search

Advanced search

Quick links