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Autocrine activation of JAK2 by IL-11 promotes platinum drug resistance

Oncogene volume 37, pages 3981–3997 (2018)Cite this article

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Abstract

Antineoplastic platinum agents are used in first-line treatment of ovarian cancer, but treatment failure frequently results from platinum drug resistance. Emerging observations suggest a role of reactive oxygen species (ROS) in the resistance of cancer drugs including platinum drugs. However, the molecular link between ROS and cellular survival pathway is poorly understood. Using quantitative high-throughput combinational screen (qHTCS) and genomic sequencing, we show that in platinum-resistant ovarian cancer elevated ROS levels sustain high level of IL-11 by stimulating FRA1-mediated IL-11 expression and increased IL-11 causes resistance to platinum drugs by constitutively activating JAK2–STAT5 via an autocrine mechanism. Inhibition of JAK2 by LY2784544 or IL-11 by anti-IL-11 antibody overcomes the platinum resistance in vitro or in vivo. Significantly, clinic studies also confirm the activated IL-11–JAK2 pathway in platinum-resistant ovarian cancer patients, which highly correlates with poor prognosis. These findings not only identify a novel ROS–IL-11–JAK2-mediated platinum resistance mechanism but also provide a new strategy for using LY2784544- or IL-11-mediated immunotherapy to treat platinum-resistant ovarian cancer.

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References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67:7–30.

    Article  PubMed  Google Scholar 

  2. Kelland L. The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer. 2007;7:573–84.

    Article  PubMed  CAS  Google Scholar 

  3. McGuire WP, Hoskins WJ, Brady MF, Kucera PR, Partridge EE, Look KY, et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med. 1996;334:1–6.

    Article  PubMed  CAS  Google Scholar 

  4. Dasari S, Tchounwou PB. Cisplatin in cancer therapy: molecular mechanisms of action. Eur J Pharmacol. 2014;740:364–78.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  5. Choi YM, Kim HK, Shim W, Anwar MA, Kwon JW, Kwon HK, et al. Mechanism of cisplatin-induced cytotoxicity is correlated to impaired metabolism due to mitochondrial ROS generation. PLoS ONE. 2015;10:e0135083.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Marullo R, Werner E, Degtyareva N, Moore B, Altavilla G, Ramalingam SS, et al. Cisplatin induces a mitochondrial-ROS response that contributes to cytotoxicity depending on mitochondrial redox status and bioenergetic functions. PLoS ONE. 2013;8:e81162.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Armstrong DK, Bundy B, Wenzel L, Huang HQ, Baergen R, Lele S, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006;354:34–43.

    Article  PubMed  CAS  Google Scholar 

  8. Burger RA, Brady MF, Bookman MA, Fleming GF, Monk BJ, Huang H, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 2011;365:2473–83.

    Article  PubMed  CAS  Google Scholar 

  9. Hanker LC, Loibl S, Burchardi N, Pfisterer J, Meier W, Pujade-Lauraine E, et al. The impact of second to sixth line therapy on survival of relapsed ovarian cancer after primary taxane/platinum-based therapy. Ann Oncol. 2012;23:2605–12.

    Article  PubMed  CAS  Google Scholar 

  10. Galluzzi L, Senovilla L, Vitale I, Michels J, Martins I, Kepp O, et al. Molecular mechanisms of cisplatin resistance. Oncogene. 2012;31:1869–83.

    Article  PubMed  CAS  Google Scholar 

  11. Wang D, Lippard SJ. Cellular processing of platinum anticancer drugs. Nat Rev Drug Discov. 2005;4:307–20.

    Article  PubMed  CAS  Google Scholar 

  12. Trachootham D, Alexandre J, Huang P. Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat Rev Drug Discov. 2009;8:579–91.

    Article  PubMed  CAS  Google Scholar 

  13. Quintas-Cardama A, Kantarjian H, Cortes J, Verstovsek S. Janus kinase inhibitors for the treatment of myeloproliferative neoplasias and beyond. Nat Rev Drug Discov. 2011;10:127–40.

    Article  PubMed  CAS  Google Scholar 

  14. Quintas-Cardama A, Verstovsek S. Molecular pathways: Jak/STAT pathway: mutations, inhibitors, and resistance. Clin Cancer Res. 2013;19:1933–40.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Buchert M, Burns CJ, Ernst M. Targeting JAK kinase in solid tumors: emerging opportunities and challenges. Oncogene. 2016;35:939–51.

    Article  PubMed  CAS  Google Scholar 

  16. Bromberg J. Stat proteins and oncogenesis. J Clin Invest. 2002;109:1139–42.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Ernst M, Putoczki TL. Molecular pathways: IL11 as a tumor-promoting cytokine-translational implications for cancers. Clin Cancer Res. 2014;20:5579–88.

    Article  PubMed  CAS  Google Scholar 

  18. Ma L, Clayton JR, Walgren RA, Zhao B, Evans RJ, Smith MC, et al. Discovery and characterization of LY2784544, a small-molecule tyrosine kinase inhibitor of JAK2V617F. Blood. Cancer J. 2013;3:e109.

    CAS  Google Scholar 

  19. Jazaeri AA, Shibata E, Park J, Bryant JL, Conaway MR, Modesitt SC, et al. Overcoming platinum resistance in preclinical models of ovarian cancer using the neddylation inhibitor MLN4924. Mol Cancer Ther. 2013;12:1958–67.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Ozols RF, Bundy BN, Greer BE, Fowler JM, Clarke-Pearson D, Burger RA, et al. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2003;21:3194–3200.

    Article  PubMed  CAS  Google Scholar 

  21. Olive PL, Banath JP. The comet assay: a method to measure DNA damage in individual cells. Nat Protoc. 2006;1:23–29.

    Article  PubMed  CAS  Google Scholar 

  22. Yu X, Vazquez A, Levine AJ, Carpizo DR. Allele-specific p53 mutant reactivation. Cancer Cell. 2012;21:614–25.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Di Veroli GY, Fornari C, Wang D, Mollard S, Bramhall JL, Richards FM, et al. Combenefit: an interactive platform for the analysis and visualization of drug combinations. Bioinformatics. 2016;32:2866–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Chou TC, Talalay P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzym Regul. 1984;22:27–55.

    Article  CAS  Google Scholar 

  25. Langdon SP, Lawrie SS, Hay FG, Hawkes MM, McDonald A, Hayward IP, et al. Characterization and properties of nine human ovarian adenocarcinoma cell lines. Cancer Res. 1988;48:6166–72.

    PubMed  CAS  Google Scholar 

  26. Wu SC, Li LS, Kopp N, Montero J, Chapuy B, Yoda A, et al. Activity of the Type II JAK2 Inhibitor CHZ868 in B Cell Acute Lymphoblastic Leukemia. Cancer Cell. 2015;28:29–41.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. James C, Ugo V, Le Couedic JP, Staerk J, Delhommeau F, Lacout C, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005;434:1144–8.

    Article  PubMed  CAS  Google Scholar 

  28. Klampfl T, Gisslinger H, Harutyunyan AS, Nivarthi H, Rumi E, Milosevic JD, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369:2379–90.

    Article  PubMed  CAS  Google Scholar 

  29. Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 2005;7:387–97.

    Article  PubMed  CAS  Google Scholar 

  30. Nangalia J, Massie CE, Baxter EJ, Nice FL, Gundem G, Wedge DC, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med. 2013;369:2391–405.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Scott LM, Tong W, Levine RL, Scott MA, Beer PA, Stratton MR, et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med. 2007;356:459–68.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Onnis B, Fer N, Rapisarda A, Perez VS, Melillo G. Autocrine production of IL-11 mediates tumorigenicity in hypoxic cancer cells. J Clin Invest. 2013;123:1615–29.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Parganas E, Wang D, Stravopodis D, Topham DJ, Marine JC, Teglund S, et al. Jak2 is essential for signaling through a variety of cytokine receptors. Cell. 1998;93:385–95.

    Article  PubMed  CAS  Google Scholar 

  34. Tyner JW, Bumm TG, Deininger J, Wood L, Aichberger KJ, Loriaux MM, et al. CYT387, a novel JAK2 inhibitor, induces hematologic responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms. Blood. 2010;115:5232–40.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Kang MA, So EY, Simons AL, Spitz DR, Ouchi T. DNA damage induces reactive oxygen species generation through the H2AX-Nox1/Rac1 pathway. Cell Death Dis. 2012;3:e249.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Tasdogan A, Kumar S, Allies G, Bausinger J, Beckel F, Hofemeister H, et al. DNA damage-induced HSPC malfunction depends on ROS accumulation downstream of IFN-1 signaling and Bid mobilization. Cell Stem Cell. 2016;19:752–67.

    Article  PubMed  CAS  Google Scholar 

  37. Park CY, Krishnan A, Zhu Q, Wong AK, Lee YS, Troyanskaya OG. Tissue-aware data integration approach for the inference of pathway interactions in metazoan organisms. Bioinformatics. 2015;31:1093–101.

    Article  PubMed  CAS  Google Scholar 

  38. Szasz AM, Lanczky A, Nagy A, Forster S, Hark K, Green JE, et al. Cross-validation of survival associated biomarkers in gastric cancer using transcriptomic data of 1,065 patients. Oncotarget. 2016;7:49322–333.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Sun W, Weingarten RA, Xu M, Southall N, Dai S, Shinn P, et al. Rapid antimicrobial susceptibility test for identification of new therapeutics and drug combinations against multidrug-resistant bacteria. Emerg Microbes Infect. 2016;5:e116

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Vichai V, Kirtikara K. Sulforhodamine B colorimetric assay for cytotoxicity screening. Nat Protoc. 2006;1:1112–6.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was partially supported by funding from the National Institutes of Health (CA177898 and CA184717 to W. Zhu), the McCormick Genomic and Proteomic Center, and intramural research program at the National Center for Advancing Translational Sciences (NCATS). W Zhu was supported by a Research Scholar Grant, RSG-13-214-01-DMC from the American Cancer Society. This work was supported by the National Natural Science Foundation of China grant 81402580 to W Zhou.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA

    Wei Zhou, Yihua Cai, Chi-Wei Chen, Yunxiao Meng, Jennifer B. Lee, Xin Cai, Zongzhu Li, Qiang Hao, Jing Hao, Huadong Pei, Zhiyong Han & Wenge Zhu

  2. Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China

    Wei Zhou, Sheng Dai, Xuefeng Huang & Zhangfa Song

  3. GW Cancer Centre, The George Washington University, Washington, DC, 20052, USA

    Wei Zhou, Yihua Cai, Chi-Wei Chen, Yunxiao Meng, Jennifer B. Lee, Yan Kai, Xin Cai, Zongzhu Li, Qiang Hao, Alexandros Tzatsos, Huadong Pei & Wenge Zhu

  4. National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, 20892, USA

    Wei Sun, Sheng Dai, John C. Braisted, Noel T. Southall, Paul Shinn & Wei Zheng

  5. Department of Obstetrics and Gynecology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China

    Mingo M. H. Yung & David W. Chan

  6. Department of Medical Oncology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China

    Yinghua Xu

  7. Department of Clinical Laboratory, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China

    Xiulei Chen

  8. Department of Physics, The George Washington University Columbian College of Arts & Sciences, Washington, DC, 20052, USA

    Yan Kai & Weiqun Peng

  9. Department of Pathology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China

    Annie N. Y. Cheung, Hextan Y. S. Ngan & Stephanie S. Liu

  10. Department of Pathology, The George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA

    Stephanie Barak

  11. Department of Oncology, the Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, 710004, China

    Zhijun Dai

  12. Department of Anatomy and Regenerative Biology, The George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA

    Alexandros Tzatsos

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  1. Wei Zhou
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Correspondence to David W. Chan, Wei Zheng or Wenge Zhu.

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These authors contributed equally: Wei Zhou, Wei Sun.

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Zhou, W., Sun, W., Yung, M.M.H. et al. Autocrine activation of JAK2 by IL-11 promotes platinum drug resistance. Oncogene 37, 3981–3997 (2018). https://doi.org/10.1038/s41388-018-0238-8

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