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Oncogene. 2018 Jul;37(29):3981-3997. doi: 10.1038/s41388-018-0238-8. Epub 2018 Apr 17.

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

Author information

1
Department of Biochemistry and Molecular Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA.
2
Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China.
3
GW Cancer Centre, The George Washington University, Washington, DC, 20052, USA.
4
National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, 20892, USA.
5
Department of Obstetrics and Gynecology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
6
Department of Medical Oncology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China.
7
Department of Clinical Laboratory, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China.
8
Department of Physics, The George Washington University Columbian College of Arts & Sciences, Washington, DC, 20052, USA.
9
Department of Pathology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
10
Department of Pathology, The George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA.
11
Department of Oncology, the Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710004, China.
12
Department of Anatomy and Regenerative Biology, The George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA.
13
Department of Obstetrics and Gynecology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China. dwchan@hku.hk.
14
National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, 20892, USA. wzheng@mail.nih.gov.
15
Department of Biochemistry and Molecular Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA. wz6812@gwu.edu.
16
GW Cancer Centre, The George Washington University, Washington, DC, 20052, USA. wz6812@gwu.edu.

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.

PMID:
29662190
PMCID:
PMC6054535
DOI:
10.1038/s41388-018-0238-8
[Indexed for MEDLINE]
Free PMC Article

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