| Literature DB >> 29662190 |
Wei Zhou1,2,3, Wei Sun4, Mingo M H Yung5, Sheng Dai2,4, Yihua Cai1,3, Chi-Wei Chen1,3, Yunxiao Meng1,3, Jennifer B Lee1,3, John C Braisted4, Yinghua Xu6, Noel T Southall4, Paul Shinn4, Xuefeng Huang2, Zhangfa Song2, Xiulei Chen7, Yan Kai3,8, Xin Cai1,3, Zongzhu Li1,3, Qiang Hao1,3, Annie N Y Cheung9, Hextan Y S Ngan9, Stephanie S Liu9, Stephanie Barak10, Jing Hao1, Zhijun Dai11, Alexandros Tzatsos3,12, Weiqun Peng8, Huadong Pei1,3, Zhiyong Han1, David W Chan13, Wei Zheng14, Wenge Zhu15,16.
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.Entities:
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Year: 2018 PMID： 29662190 PMCID： PMC6054535 DOI： 10.1038/s41388-018-0238-8
Source DB: PubMed Journal: Oncogene ISSN： 0950-9232 Impact factor: 9.867