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

doi:10.1016/j.canlet.2018.04.029

Cancer Letters

Volume 428, 1 August 2018, Pages 104-116

https://doi.org/10.1016/j.canlet.2018.04.029 Get rights and content

Highlights

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Providing multiple potential approaches for treatment of platinum resistant ovarian cancer.
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Integrating qHTCS, RNA-seq and clinical studies to elucidate cisplatin resistant mechanism.
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DUOXA1-mediated activation of ATR-Chk1 regulates cisplatin resistance in ovarian cancer.

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.

Introduction

Accumulating evidence has showed that most of advanced ovarian cancer patients have a good response to initial therapy with combination of cytoreductive surgery and platinum-based chemotherapy [1]. However, approximately 70% of patients will develop resistance to platinum drugs over the time of treatment [2,3]. Multiple mechanisms have been identified to regulate platinum-resistance [4]. Among them, increased DNA damage response is positively correlated with platinum-resistance [[5], [6], [7]]. However, the mechanism of sustaining the high activity of DNA damage response in platinum resistant ovarian cancer cells remains largely unknown.

Reactive oxygen species (ROS) is composed of free radicals and reactive metabolites, such as superoxide, hydroxyl radical, and hydroxide [8]. Emerging evidence has shown that ROS act as a double-edged sword in living organisms [9]. Low dose of ROS is able to promote cell proliferation, mediate cell signal transduction, and under certain circumstance can promote cellular survival and tumor growth [[10], [11], [12]]. In contrast, excessive amount of ROS is capable of causing cellular damage on lipid, DNA, RNA and proteins [13]. In cancer cells, increased ROS accumulation can be resulted from activation of oncogenes [[14], [15], [16]]. Several proteins are well-known in regulating ROS production, including FOXM1, DPP4, PTPN11, ABL1, and Dual oxidase 1 (DUOX1) [[15], [16], [17], [18], [19]]. Dual oxidase 1 (DUOX1) is composed of DUOXA1 and DUOXA2 [20,21]. DUOX1 has been shown to mediate thyroid hormonogenesis through production of hydrogen peroxide [22]. It was also reported that overexpression of DUOXA1 inhibits murine muscle satellite cell differentiation by raising ROS production [19].

It is well documented that platinum drugs kill cancer cells by introducing DNA crosslinks via covalent bond between DNA bases and thereby, reducing cell viability [23]. FANCD2 and other members of Fanconi anemia family play a critical role in repairing DNA crosslink damage. Activation of FANCD2 is regulated through its mono-ubiquitination [[24], [25], [26], [27]]. ATR (ataxia telangiectasia and Rad3-related protein) is a serine/threonine protein kinase that is essential to regulate DNA damage response in cells with DNA crosslinks [28]. In cells with DNA crosslinks, ATR activates Checkpoint kinase 1 (Chk1) by phosphorylation of at Ser-317 and Ser-345 [29]. Chk1 is important to mediate DNA damage repair by activating repair factors such as Rad51, FANCE and PCNA [30].

To identify the novel mechanism regulating cisplatin resistance, we conducted a quantitative high throughput combinational screen (qHTCS) together with RNA-sequencing (RNA-seq) in cisplatin resistant ovarian cancer cells [31,32]. From this qHTCS, we identified two Chk1 inhibitors (PF-477736 and AZD7762) that synergistically enhanced cisplatin efficacy against cisplatin resistant ovarian cancer cells. Significantly, we found DOUXA1 was up-regulated in platinum-resistant cells and elevated DOUXA1 increased ROS levels, which sustained the active ATR-Chk1 pathway. Inhibition of ROS, DUOXA1, ATR or Chk1 effectively overcame cisplatin resistance in vitro or in vivo. The clinical studies also confirmed the activation of ATR and DUOXA1 in recurrent and resistant ovarian cancer patients, and elevated ATR-Chk1 or DOUXA1 was correlated with poor prognosis in ovarian cancer patients who have received platinum drug-based therapy.

Section snippets

Cell lines and generation of resistant cells

SKOV3 was from the American Type Culture Collection (ATCC). PEO14 and PEO23 were from Sigma-Aldrich. SKOV3 was cultured in Dulbecco's Modified Eagle's medium supplemented with 10% fetal bovine serum (FBS). PEO14 and PEO23 were cultured in RPMI-1640 supplemented with 10% FBS. Establishment of cisplatin resistant cell line SKOV3 CR was as described previously [33]. Details were provided in Appendix S1 (Supplementary methods).

Cell viability assay

Cell viability and IC₅₀ were measured as previous descriptions [34] [35

qHTCS and RNA-seq to identify Chk1 inhibitors that overcome cisplatin resistance in ovarian cancer cells

The main goal of this study is to integrate two platforms, qHTCS and genomic sequencing, to identify novel mechanisms regulating platinum-resistance in ovarian cancer and small molecules that can overcome platinum resistance in ovarian cancer cells. The identified pathways will be further confirmed by in vivo as well as clinical studies (Fig. 1A). We first generated the cisplatin resistant cells using procedures as described previously and in methods [41,42]. A resistant cell line, SKOV3 CR,

Discussion

In this study, we used an unbiased qHTCS assay to identify Chk1 inhibitors that re-sensitize cisplatin resistant ovarian cancer cells to cisplatin. Subsequent analyses identified elevated DUOXA1 as a driving force for activating and sustaining high level of ROS, which promotes cisplatin resistance by activating ATR-Chk1 pathway (Fig. 7E). Importantly, we provided the clinical evidence showing that activated ATR and DUOXA1 are found in platinum-resistant tumor tissues of ovarian cancer patients

Author contributions

Y.M., C.C., W.S., W. Zheng, D.W.C., W. Zhu contributed to design experiments, interpret results, and write the manuscript. Y.M., C.C., W.S., W. Zhou, J.L., J.S., Zhuqing Li, Zongzhu Li., J.C.B., Y.K., W.P., A.T., Y.L., Z.D., contributed to perform experiments. M.M.Y., S.S.L., A.N.C., H.Y.N., D.W.C., contributed to collection and analyze the samples from patients. W. Zheng and W. Zhu supervised the project and acquired funding. All authors assisted in editing the manuscript and approved it

Conflicts of interest

None to declare.

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.

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Original ArticlesDUOXA1-mediated ROS production promotes cisplatin resistance by activating ATR-Chk1 pathway in ovarian cancer

Highlights

Abstract

Introduction

Section snippets

Cell lines and generation of resistant cells

Cell viability assay

qHTCS and RNA-seq to identify Chk1 inhibitors that overcome cisplatin resistance in ovarian cancer cells

Discussion

Author contributions

Conflicts of interest

Acknowledgements

Ann. Oncol.

Canc. Cell

J. Biol. Chem.

Eur. J. Pharmacol.

Mol. Cell.

Trends Biochem. Sci.

Methods

Adv. Enzym. Regul.

Neoplasia

Exp. Cell Res.

Toxicol. Appl. Pharmacol.

Biochem. Biophys. Res. Commun.

Cytoreductive surgery plus platinum-based hyperthermic intraperitoneal chemotherapy in epithelial ovarian cancer: a promising integrated approach to improve locoregional control

Oncology

Systems biology of cisplatin resistance: past, present and future

Cell Death Dis.

Molecular mechanisms of cisplatin resistance

Oncogene

Platinum resistance: the role of DNA repair pathways

Clin. Canc. Res.

Resistance to chemotherapy in advanced ovarian cancer: mechanisms and current strategies

Br. J. Canc.

Ovarian cancer: strategies for overcoming resistance to chemotherapy

Nat. Rev. Canc.

Oxidative stress: oxidants and antioxidants

Exp. Physiol.

Reactive oxygen species as double-edged swords in cellular processes: low-dose cell signaling versus high-dose toxicity

Hum. Exp. Toxicol.

Hypoxia-inducible factors are required for chemotherapy resistance of breast cancer stem cells

Proc. Natl. Acad. Sci. U. S. A.

Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach?

Nat. Rev. Drug Discov.

Reactive oxygen species: a breath of life or death?

Clin. Canc. Res.

Oxidant signaling in vascular cell growth, death, and survival : a review of the roles of reactive oxygen species in smooth muscle and endothelial cell mitogenic and apoptotic signaling

Circ. Res.

FoxM1, a critical regulator of oxidative stress during oncogenesis

EMBO J.

Long-term treatment with Sitagliptin, a dipeptidyl peptidase-4 inhibitor, reduces colon carcinogenesis and reactive oxygen species in 1,2-dimethylhydrazine-induced rats

Int. J. Canc.

Activating mutations in protein tyrosine phosphatase Ptpn11 (Shp2) enhance reactive oxygen species production that contributes to myeloproliferative disorder

PLoS One

Dual oxidase maturation factor 1 (DUOXA1) overexpression increases reactive oxygen species production and inhibits murine muscle satellite cell differentiation

Cell Commun. Signal.

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