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NF-Kb and Poly (ADP-Ribose) Polymerase 1 Form a Positive

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NF-Kb and Poly (ADP-Ribose) Polymerase 1 Form a Positive Published OnlineFirst December 17, 2018; DOI: 10.1158/1541-7786.MCR-18-0523 Genome Maintenance Molecular Cancer Research NF-kB and Poly (ADP-ribose) Polymerase 1 Form a Positive Feedback Loop that Regulates DNA Repair in Acute Myeloid Leukemia Cells Ding Li1, Yufei Luo1, Xianling Chen2, LingYu Zhang1, Tingting Wang1, Yingting Zhuang3, Yingjuan Fan3, Jianhua Xu1,3,4, Yuanzhong Chen2, and Lixian Wu1,3,4 Abstract NF-kB mediates acquired resistance in acute myeloid DNA repair. Simultaneous treatment with the NF-kB inhib- leukemia (AML) cells treated with DNA-damaging agents. itor BMS-345541 and the PARP1 inhibitor olaparib resulted Because DNA repair is the major molecular shift that alters in robust killing of AML cells. This dual inhibition signif- sensitivity to DNA-damaging agents, we explored whether icantly suppressed tumor growth and extended survival activation of the NF-kB pathway promotes AML cell survival times in xenograft tumor models. by regulating DNA repair after chemotherapy. Our results showed that RELA, an important subunit of NF-kB, regu- Implications: RELA and PARP1 form a positive feedback loop lated DNA repair by binding to the promoter region of the to regulate DNA damage repair, simultaneous inhibition of PARP1 gene and affecting PARP1 gene transcription. Con- NF-kB and PARP1 increases the antileukemic efficacy of dau- versely, PARP1 knockdown reduced NF-kB activity, indicat- norubicin in vitro and in vivo, broadening the use of PARP1 ing that NF-kB and PARP1 create a positive feedback loop in inhibitors. inhibit DNA repair as a rational sensitization method to improve Introduction genotoxicity therapy. Acute myeloid leukemia (AML) is a highly aggressive hemato- Constitutive NF-kB pathway activation has been found in logic malignancy characterized by the overproduction of imma- different types of AML (5). DNA-damaging agents activate ture white blood cells (1). Despite important advances in our NF-kB initiating in the nucleus instead of via membrane-bound understanding of the molecular basis of AML, survival outcomes receptors (6–8). NF-kB activation induced by DNA damage is of patients with AML have not improved over the past 20 years (2), necessary for secondary resistance in AML cells (9, 10). Because indicating the need to develop novel therapies that are more efficient repair of DNA damage is required for the survival of effective and less toxic. AML cells (11, 12), we investigated whether NF-kB pathway DNA damage is the common mechanism induced by radio- activation also regulates DNA repair to promote cell survival therapy and chemotherapy in the clinical treatment of cancer (3). after chemotherapy. Although therapy-induced DNA damage is widespread, AML cells PARP1 is a nuclear protein that is mainly known for its ability to utilize endogenous DNA repair mechanisms to enable their facilitate DNA repair by catalyzing the poly ADP-ribosylation survival, recurrence, and resistance (4). In addition, enhancement (PARylation) of itself and other repair-associated proteins of DNA repair pathways in chemotherapeutic-resistant AML cells (13, 14). PARP1 hyperactivation in DNA repair is critical for the is often considered as the major molecular change that alters its resistance to genotoxic agents, which has been confirmed not only sensitivity to DNA-damaging agents. Given the key roles of DNA in cancer cell lines and xenografts, but also in several clinical repair pathways in chemoresistance, it has been proposed to studies (15–17). In addition, PARP1 inhibitors are a new type of anticancer drugs that selectively kills cancer cells with homolo- gous recombination (HR) repair defects (18, 19). However, 1 deficient HR and the rapid emergence of resistance have largely Department of Pharmacology, School of Pharmacy, Fujian Medical University, – Fuzhou, P.R. China. 2Fujian Institute of Hematology, Union Hospital, Fujian limited the clinic usage of PARP1 inhibition (20 22). Thus, there Medical University, Fuzhou, P.R. China. 3Institute of Materia Medica, Fujian is an urgent need to develop novel therapeutic approaches to Medical University, Fuzhou, P.R. China. 4Fuijan Key Laboratory of Natural extend the efficacy of PARP1 inhibitor–based therapies. Medicine Pharmacology, Fujian Medical University, Fuzhou, P.R. China. Because both NF-kB and PARP1 activities are indispensable to Note: Supplementary data for this article are available at Molecular Cancer the establishment of resistance to genotoxic agents, we sought to Research Online (http://mcr.aacrjournals.org/). explore the regulatory link between these two DNA repair com- Corresponding Authors: Lixian Wu, Fujian Medical University, 1 Xueyuan Road, ponents. Previous work identified NF-kB as a component of the Fuzhou 350108, Fujian, China. Phone: 86-1825-9000-966; Fax: 86-591-8356-9307; DNA damage signaling pathway initiated by PARP1 and ATM that E-mail: [email protected]; and Yuanzhong Chen, Fujian Institute of Hematology, leads to IKKg phosphorylation, inhibitor kBa (IkBa) degrada- Union Hospital, Fujian Medical University, Fuzhou 350004, Fujian, China. Phone: tion, and ultimately nuclear translocation of the NF-kB subunit 86-591-8711-3828; Fax: 86-591-8711-3828; E-mail: [email protected] RELA (23–25). Conversely, here we showed that RELA knock- doi: 10.1158/1541-7786.MCR-18-0523 down causes the downregulation of PARP1 expression. Our Ó2018 American Association for Cancer Research. results demonstrate that NF-kB, as a critical transcription factor www.aacrjournals.org 761 Downloaded from mcr.aacrjournals.org on September 24, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst December 17, 2018; DOI: 10.1158/1541-7786.MCR-18-0523 Li et al. for the DNA damage response, can regulate PARP1 transcription Confocal microscopy analysis of gH2AX foci and thus form a feedback loop. On the basis of this mechanism, The confocal microscopy assay was performed as described we showed that combining a PARP inhibitor with an NF-kB previously (29). Briefly, after washing with ice-cold PBS, cells were inhibitor resulted in robust synergy in in vitro and in vivo AML fixed, permeabilized, and incubated with gH2AX antibodies models by decreasing DNA repair efficacy and increasing DNA (Thermo Fisher Scientific, catalog no LF-PA0025) and fluores- damage accumulation and apoptosis induction. These findings cence-labeled secondary antibodies. Immunostained cells were suggest that dual inhibition of NF-kB and PARP1 may be an examined using a Leica Laser-Scanning Microscope (TCS SP8) effective approach to increase the efficacy of DNA damage agents with a 63X/1.4 objective. Image quantification was performed such as daunorubicin by blocking DNA repair jointly in AML using ImageJ software (NIH, Bethesda, MD). therapy. Neutral comet assay Cells were processed for neutral comet assay using a Comet Materials and Methods Assay Kit from Trevigen (catalog no ADI-900-166), according the Cell culture manufacturer's protocol. Approximately 50 nucleus images per The AML cell lines KG1a and Kasumi-1 were obtained from slide were captured and processed by a Zeiss Axio Observer Z1 ATCC, where they were characterized by DNA fingerprinting, Microscope (Carl Zeiss). The tail moments from the cells were Mycoplasma detection, and cell vitality detection. These cell lines measured by CASP software. were immediately expanded and frozen. They were cultured in complete Iscove's modified Dulbecco's medium (IMDM; Gibco) qRT-PCR and RPMI1640 medium (Gibco), respectively, each medium Total RNA was extracted using BIOzol Reagent (BioFlux, cat- was supplemented with 10% FBS (Gibco) and 1% penicillin– alog no BSC52M1), and cDNA was synthesized with a PrimeScript streptomycin. The cells were maintained in a humidified incuba- RT Reagent Kit (Takara Bio, catalog no RR047A). qPCR was tor at 37 C with 5% CO2. performed in triplicate on a LightCycler 96 Real-Time PCR System (Roche, G10120-100G) with SYBR Premix Ex Taq (Takara Bio, Reagents catalog no RR420A). Relative expression was normalized to that À C The IKKb inhibitor BMS-345541 (BMS) and the PARP1 inhib- of GAPDH by the 2 DD t method. The primers used in this study itor olaparib were obtained from Meilunbio Co., Ltd. BMS and are shown in Supplementary Table S1. olaparib were separately dissolved in dimethyl sulfoxide to achieve a concentration of 20 mmol/L, and then each solution Western blotting was serially diluted to specific concentrations. Daunorubicin was Western blotting was performed according to standard proto- purchased from Zhejiang Hisun Pharmaceutical Co., Ltd. cols using a Chemiluminescence Detection System from Clinx Science Instruments. The following primary antibodies were HR repair assays used: anti-RELA (Proteintech, catalog no 10745-1-AP), anti-PAR HR repair was measured in AML/DR-GFP cells, according to the (Calbiochem, catalog no AM80), and anti-PARP1 (Santa Cruz previous publications as shown in Fig. 2A (26, 27). Specifically, Biotechnology, catalog no sc-8007), as well as goat anti-rabbit 6 Â 105 AML cells were cotransfected with 2 mg of pDR-GFP (Proteintech, catalog no SA100001-2) or anti-mouse secondary (Addgene, catalog no 46085) and 2 mg of pCBASceI (Addgene, antibodies (Proteintech, catalog no SA00001-1). Expression catalog no26477) plasmid DNA using Nucleofector solution and levels were normalized to those of the GAPDH mouse mAB the appropriate Nucleofector program. After 48 hours of trans- (Proteintech, catalog no 60004-1-Ig); these antibodies were used fection, the cells were incubated with daunorubicin for 2 hours,
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