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Cancer Lett. 2018 Aug 1;428:104-116. doi: 10.1016/j.canlet.2018.04.029. Epub 2018 Apr 26.

DUOXA1-mediated ROS production promotes cisplatin resistance by activating ATR-Chk1 pathway in ovarian cancer.

Author information

1
Department of Biochemistry and Molecular Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA; GW Cancer Center, The George Washington University, Washington, DC, 20052, USA.
2
Department of Obstetrics and Gynecology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
3
National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, 20892, USA.
4
Department of Biochemistry and Molecular Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA; GW Cancer Center, The George Washington University, Washington, DC, 20052, USA; Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China.
5
Department of Pathology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
6
GW Cancer Center, The George Washington University, Washington, DC, 20052, USA; Department of Physics, The George Washington University Columbian College of Arts & Sciences, Washington, DC, 20052, USA.
7
Department of Physics, The George Washington University Columbian College of Arts & Sciences, Washington, DC, 20052, USA.
8
GW Cancer Center, The George Washington University, Washington, DC, 20052, USA; Department of Anatomy and Regenerative Biology, The George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA.
9
Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College & Chinese Academy of Medical Sciences, Tianjin, 300192, China.
10
Department of Oncology, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710004, China.
11
National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, 20892, USA. Electronic address: wzheng@mail.nih.gov.
12
Department of Obstetrics and Gynecology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China. Electronic address: dwchan@hku.hk.
13
Department of Biochemistry and Molecular Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA; GW Cancer Center, The George Washington University, Washington, DC, 20052, USA. Electronic address: wz6812@gwu.edu.

Abstract

The acquisition of resistance is a major obstacle to the clinical use of platinum drugs for ovarian cancer treatment. Increase of DNA damage response is one of major mechanisms contributing to platinum-resistance. However, how DNA damage response is regulated in platinum-resistant ovarian cancer cells remains unclear. Using quantitative high throughput combinational screen (qHTCS) and RNA-sequencing (RNA-seq), we show that dual oxidase maturation factor 1 (DUOXA1) is overexpressed in platinum-resistant ovarian cancer cells, resulting in over production of reactive oxygen species (ROS). Elevated ROS level sustains the activation of ATR-Chk1 pathway, leading to resistance to cisplatin in ovarian cancer cells. Moreover, using qHTCS we identified two Chk1 inhibitors (PF-477736 and AZD7762) that re-sensitize resistant cells to cisplatin. Blocking this novel pathway by inhibiting ROS, DUOXA1, ATR or Chk1 effectively overcomes cisplatin resistance in vitro and in vivo. Significantly, the clinical studies also confirm the activation of ATR and DOUXA1 in ovarian cancer patients, and elevated DOUXA1 or ATR-Chk1 pathway correlates with poor prognosis. Taken together, our findings not only reveal a novel mechanism regulating cisplatin resistance, but also provide multiple combinational strategies to overcome platinum-resistance in ovarian cancer.

KEYWORDS:

ATR-Chk1; Cisplatin resistance; DUOXA1; High throughput screen; Ovarian cancer; ROS

PMID:
29704517
DOI:
10.1016/j.canlet.2018.04.029
[Indexed for MEDLINE]

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