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Abiraterone and MDV3100 Inhibits the Proliferation and Promotes The Han et al. Cancer Cell Int (2019) 19:332 https://doi.org/10.1186/s12935-019-1021-9 Cancer Cell International PRIMARY RESEARCH Open Access Abiraterone and MDV3100 inhibits the proliferation and promotes the apoptosis of prostate cancer cells through mitophagy Jingli Han1† , Junhua Zhang1†, Wei Zhang2, Dalei Zhang3, Ying Li1, Jinsong Zhang2, Yaqun Zhang3, Tongxiang Diao3, Luwei Cui3, Wenqing Li1, Fei Xiao1,2,4, Ming Liu3* and Lihui Zou1* Abstract Background: Abiraterone and MDV3100 are two efective anticancer agents for prostate cancer, however, the mechanism of their downstream action remains undefned. Methods: A dual fuorescent biosensor plasmid was transfected in LNCaP cells to measure mitophagy. The DNA of LNCaP cells was extracted and performed with quantitative real-time PCR to detect mitochondrial DNA copy number. JC-1 staining was utilized to detect the mitochondrial membrane potential and electron microscope was performed to analyze mitochondrial morphology. Moreover, the protein levels of mitochondrial markers and apoptotic markers were detected by western blot. At last, the proliferation and apoptosis of LNCaP cells were analyzed with CCK-8 assay and fow cytometry after abiraterone or MDV3100 treatment. Results: Mitophagy was induced by abiraterone and MDV3100 in LNCaP cells. The low expression level of mito- chondrial DNA copy number and mitochondrial depolarization were further identifed in the abiraterone or MDV3100 treatment groups compared with the control group. Besides, severe mitochondria swelling and substantial autophagy-lysosomes were observed in abiraterone- and MDV3100-treated LNCaP cells. The expression of mito- chondria-related proteins, frataxin, ACO2 and Tom20 were signifcantly downregulated in abiraterone and MDV3100 treated LNCaP cells, whereas the expression level of inner membrane protein of mitochondria (Tim23) was signif- cantly upregulated in the same condition. Moreover, the proliferation of LNCaP cells were drastically inhibited, and the apoptosis of LNCaP cells was increased in abiraterone or MDV3100 treatment groups. Meanwhile, the addition of mitophagy inhibitor Mdivi-1 (mitochondrial division inhibitor 1) could conversely elevate proliferation and constrain apoptosis of LNCaP cells. Conclusions: Our results prove that both abiraterone and MDV3100 inhibit the proliferation, promote the apoptosis of prostate cancer cells through regulating mitophagy. The promotion of mitophagy might enhance the efcacy of abiraterone and MDV3100, which could be a potential strategy to improve chemotherapy with these two reagents. Keywords: Prostate cancer, Mitophagy, Abiraterone, MDV3100 *Correspondence: [email protected]; [email protected] †Jingli Han and Junhua Zhang contributed equally to this work 1 The MOH Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Beijing 100730, People’s Republic of China 3 Department of Urology, Beijing Hospital, National Center of Gerontology, Beijing 100730, People’s Republic of China Full list of author information is available at the end of the article © The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Han et al. Cancer Cell Int (2019) 19:332 Page 2 of 10 Background was named as pDsRed-Mito-Rosella, which determines Prostate cancer (PCa) is one of the most common carci- mitophagy with reduced green to red fuorescent ratio. nomas in men with promptly increasing incidence rate Human prostate adenocarcinoma cells lymph node car- and high mortality in the past decade [1]. Abiraterone cinoma of the prostate (LNCaP) with high expression acetate, the precursor of abiraterone, is an androgen bio- of AR has long been considered as the closest model for synthesis inhibitor which is used in the treatment of pros- prostate cancer study, and its proliferation depends on tate cancer, specifcally in combination with castration the activation of androgen receptor signaling pathway. It and prednisone for the treatment of metastatic castra- can be used to investigate the downstream mechanism tion-resistant prostate cancer (mCRPC) and metastatic of abiraterone and MDV3100 in the treatment of pros- high-risk castration-sensitive prostate cancer (mCSPC) tate cancer [17]. Here, we found that abiraterone and [2, 3]. Abiraterone also antagonizes androgen recep- MDV3100 induced mitophagy measured via the plasmid tor (AR), which plays a crucial role in the progression of pDsRed-Mito-Rosella biosensor, which was consistent prostate cancer [4, 5]. MDV3100, the second-generation with further identifcation of canonical mitophagy, mito- antiandrogen enzalutamide, is another efective drug for chondrial membrane depolarization, mitochondria swell- treatment of prostate cancer. MDV3100 binds directly ing, and decreased expression of crucial mitochondrial to AR and competitively inhibits androgen binding, thus proteins such as ACO2, frataxin and ATP synthetase. hampers AR nuclear translocation and AR-mediated Moreover, the proliferation of prostate cancer cells was DNA binding [4, 6]. MDV3100 also has a therapeutic inhibited and the apoptosis of prostate cancer cells was efect on CRPC with elevated AR expression and non- promoted, both of which were converted by mitophagy metastatic CRPC with increased prostate-specifc anti- inhibitor Mdivi-1. gen (PSA) level [7, 8]. Over the past decade, many studies have demonstrated Materials and methods that autophagy and mitophagy were frequently induced Cell culture and transfection by anticarcinogens under the stimulation of multiple LNCaP cells purchased from American Type Culture forms of cellular stresses [9, 10]. Autophagy is a con- Collection (ATCC) were cultured in RPMI-1640 medium served homeostatic pathway that degrades damaged pro- (Gbico, Termo Fisher Scientifc, USA) supplemented teins or organelles through the formation of autophagic with 10% fetal bovine serum (HyClone Inc., Utah, USA) lysosomes with a two-membrane compartment [11]. and incubated at 37 °C with 5% CO2. Te exponentially Mitophagy is a type of autophagy, which maintains the growing LNCaP cells were treated with 20 nmol/L abi- quality of mitochondria and maintains the health of cells raterone (Aladdin Industral Corp., Shanghai, China) for by scavenging aged and damaged mitochondria [12, 13]. 24 h or 10 nmol/L MDV3100 (MedChem Express, Shang- Moreover, mitophagy would further activate autophagy hai, China) for 48 h or 20 μmol/L mdivi-1(MedChem which is important for the regulation of cancer progres- Express, Shanghai, China). Te plasmids, pDsRed- sion and helps to determine how cancer cells respond to Rosella-LC3, pDsRed-Mito-Rosella and pDsRed-NC anticancer therapies [9, 14]. Terefore, the promotion or were constructed in our laboratory referred the study of suppression of mitophagy might be a potential strategy Sargsyan et al. [16] and some alterations were made. Plas- for clinical therapy. Although the roles of abiraterone and mid Rosella-LC3 consists of the complete open reading MDV3100 in anti-tumor activity have been reported [2, frame (ORF) of human LC3B (Map1lc3b) joined in frame 14], the relationship between them and mitochondrial with the 3′ end of the Rosella ORF (coding the C-termi- functions, especially mitophagy, in prostate cancer cells nus) without a stop codon. Plasmid Mito-Rosella consists is still unclear. of the subunit VIII of cytochrome c oxidase (COX8) ORF In this paper, we used a plasmid that can co-express without a stop codon fused in frame with the 5′ end of mitochondrial associated protein subunit VIII of the Rosella ORF (coding the N-terminus). LNCaP cells cytochrome c oxidase (COX8) [15], non-pH-sensitive were seeded in 6-well dish and transfected with plasmid discosoma red fuorescent protein (DsRed), and pH-sen- (2.5 μg/well) using lipofectamine 3000 reagent (Invitro- sitive green fuorescent protein (pHluorin), which can be gen, Termo Fisher Scientifc, USA) in accordance with used to detect mitophagy in cells because the intracel- standard experimental procedure. lular pH was reduced when mitophagy occurs [16]. Te combination of DsRed and pHluorin was called Rosella, Confocal microscopy assay while COX8 is one of the mitochondria-specifc proteins. To determine mitophagy or autophagy in LNCaP cells, Te intensity of pHluorin changed due to intracellular they were exposed to abiraterone or MDV3100 after 48 h pH in eukaryotic cells, while the intensity of DsRed did transfection, then the nuclei were stained with 1 μg/mL not. Te constructed plasmid used to measure mitophagy DAPI (Termo Fisher Scientifc, USA) for 30 min. Te Han et al. Cancer Cell Int (2019) 19:332 Page 3 of 10 fuorescence changes in response to drugs or vehicle were blocked with 5% skimmed milk. All kinds of anti- treatment were observed and measured in more than 25 bodies were diluted by antibody dilution solution (Beyo- felds with a confocal fuorescence microscope (Nikon, time Biotech, Haimen, China) and were incubated under Japan) at 10× 40 magnifcation. Vehicle-treated cells the manual instruction. served as a
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