ARV-825 Demonstrates Antitumor Activity in Gastric Cancer via MYC-Targets and G2M-Checkpoint Signaling Pathways
ObjectiveSuppression of bromodomain and extra terminal (BET) proteins has a bright prospect to treat MYC-driven tumors. Bromodomain containing 4 (BRD4) is one of the BET proteins. ARV-825, consisting of a BRD4 inhibitor conjugated with a cereblon ligand using proteolysis-targeting chimera (PROTAC) t...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2021-10-01
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| Series: | Frontiers in Oncology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2021.753119/full |
| _version_ | 1818926269244375040 |
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| author | Xinmei Liao Xiaoqing Qian Xiaoqing Qian Zimu Zhang Yanfang Tao Zhiheng Li Qian Zhang Hui Liang Xiaolu Li Yi Xie Ran Zhuo Yanling Chen You Jiang Haibo Cao Jiaqi Niu Cuili Xue Jian Ni Jian Pan Daxiang Cui Daxiang Cui |
| author_facet | Xinmei Liao Xiaoqing Qian Xiaoqing Qian Zimu Zhang Yanfang Tao Zhiheng Li Qian Zhang Hui Liang Xiaolu Li Yi Xie Ran Zhuo Yanling Chen You Jiang Haibo Cao Jiaqi Niu Cuili Xue Jian Ni Jian Pan Daxiang Cui Daxiang Cui |
| author_sort | Xinmei Liao |
| collection | DOAJ |
| description | ObjectiveSuppression of bromodomain and extra terminal (BET) proteins has a bright prospect to treat MYC-driven tumors. Bromodomain containing 4 (BRD4) is one of the BET proteins. ARV-825, consisting of a BRD4 inhibitor conjugated with a cereblon ligand using proteolysis-targeting chimera (PROTAC) technology, was proven to decrease the tumor growth effectively and continuously. Nevertheless, the efficacy and mechanisms of ARV-825 in gastric cancer are still poorly understood.MethodsCell counting kit 8 assay, lentivirus infection, Western blotting analysis, Annexin V/propidium iodide (PI) staining, RNA sequencing, a xenograft model, and immunohistochemistry were used to assess the efficacy of ARV-825 in cell level and animal model.ResultsThe messenger RNA (mRNA) expression of BRD4 in gastric cancer raised significantly than those in normal tissues, which suggested poor outcome of patients with gastric cancer. ARV-825 displayed higher anticancer efficiency in gastric cancer cells than OTX015 and JQ1. ARV-825 could inhibit cell growth, inducing cell cycle block and apoptosis in vitro. ARV-825 induced degradation of BRD4, BRD2, BRD3, c-MYC, and polo-like kinase 1 (PLK1) proteins in four gastric cancer cell lines. In addition, cleavage of caspase 3 and poly-ADP-ribose polymerase (PARP) was elevated. Knockdown or overexpression CRBN could increase or decrease, respectively, the ARV-825 IC50 of gastric cancer cells. ARV-825 reduced MYC and PLK1 expression in gastric cancer cells. ARV-825 treatment significantly reduced tumor growth without toxic side effects and downregulated the expression of BRD4 in vivo.ConclusionsHigh mRNA expression of BRD4 in gastric cancer indicated poor prognosis. ARV-825, a BRD4 inhibitor, could effectively suppress the growth and elevate the apoptosis of gastric cancer cells via transcription downregulation of c-MYC and PLK1. These results implied that ARV-825 could be a good therapeutic strategy to treat gastric cancer. |
| first_indexed | 2024-12-20T02:54:26Z |
| format | Article |
| id | doaj.art-f7e01e8efd95499b95c85efc1e1cca52 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-20T02:54:26Z |
| publishDate | 2021-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-f7e01e8efd95499b95c85efc1e1cca522022-12-21T19:55:58ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2021-10-011110.3389/fonc.2021.753119753119ARV-825 Demonstrates Antitumor Activity in Gastric Cancer via MYC-Targets and G2M-Checkpoint Signaling PathwaysXinmei Liao0Xiaoqing Qian1Xiaoqing Qian2Zimu Zhang3Yanfang Tao4Zhiheng Li5Qian Zhang6Hui Liang7Xiaolu Li8Yi Xie9Ran Zhuo10Yanling Chen11You Jiang12Haibo Cao13Jiaqi Niu14Cuili Xue15Jian Ni16Jian Pan17Daxiang Cui18Daxiang Cui19Institute of Nano Biomedicine and Engineering, Shanghai Engineering Research Centre for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai, ChinaInstitute of Nano Biomedicine and Engineering, Shanghai Engineering Research Centre for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai, ChinaSchool of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, ChinaInstitute of Pediatric Research, Children’s Hospital of Soochow University, Suzhou, ChinaInstitute of Pediatric Research, Children’s Hospital of Soochow University, Suzhou, ChinaInstitute of Pediatric Research, Children’s Hospital of Soochow University, Suzhou, ChinaInstitute of Nano Biomedicine and Engineering, Shanghai Engineering Research Centre for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai, ChinaInstitute of Nanomedicine, National Engineering Research Centre for Nanotechnology, Shanghai, ChinaInstitute of Pediatric Research, Children’s Hospital of Soochow University, Suzhou, ChinaInstitute of Pediatric Research, Children’s Hospital of Soochow University, Suzhou, ChinaInstitute of Pediatric Research, Children’s Hospital of Soochow University, Suzhou, ChinaInstitute of Pediatric Research, Children’s Hospital of Soochow University, Suzhou, ChinaInstitute of Pediatric Research, Children’s Hospital of Soochow University, Suzhou, ChinaInstitute of Pediatric Research, Children’s Hospital of Soochow University, Suzhou, ChinaInstitute of Nano Biomedicine and Engineering, Shanghai Engineering Research Centre for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai, ChinaInstitute of Nano Biomedicine and Engineering, Shanghai Engineering Research Centre for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai, ChinaInstitute of Nano Biomedicine and Engineering, Shanghai Engineering Research Centre for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai, ChinaInstitute of Pediatric Research, Children’s Hospital of Soochow University, Suzhou, ChinaInstitute of Nano Biomedicine and Engineering, Shanghai Engineering Research Centre for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai, ChinaInstitute of Nanomedicine, National Engineering Research Centre for Nanotechnology, Shanghai, ChinaObjectiveSuppression of bromodomain and extra terminal (BET) proteins has a bright prospect to treat MYC-driven tumors. Bromodomain containing 4 (BRD4) is one of the BET proteins. ARV-825, consisting of a BRD4 inhibitor conjugated with a cereblon ligand using proteolysis-targeting chimera (PROTAC) technology, was proven to decrease the tumor growth effectively and continuously. Nevertheless, the efficacy and mechanisms of ARV-825 in gastric cancer are still poorly understood.MethodsCell counting kit 8 assay, lentivirus infection, Western blotting analysis, Annexin V/propidium iodide (PI) staining, RNA sequencing, a xenograft model, and immunohistochemistry were used to assess the efficacy of ARV-825 in cell level and animal model.ResultsThe messenger RNA (mRNA) expression of BRD4 in gastric cancer raised significantly than those in normal tissues, which suggested poor outcome of patients with gastric cancer. ARV-825 displayed higher anticancer efficiency in gastric cancer cells than OTX015 and JQ1. ARV-825 could inhibit cell growth, inducing cell cycle block and apoptosis in vitro. ARV-825 induced degradation of BRD4, BRD2, BRD3, c-MYC, and polo-like kinase 1 (PLK1) proteins in four gastric cancer cell lines. In addition, cleavage of caspase 3 and poly-ADP-ribose polymerase (PARP) was elevated. Knockdown or overexpression CRBN could increase or decrease, respectively, the ARV-825 IC50 of gastric cancer cells. ARV-825 reduced MYC and PLK1 expression in gastric cancer cells. ARV-825 treatment significantly reduced tumor growth without toxic side effects and downregulated the expression of BRD4 in vivo.ConclusionsHigh mRNA expression of BRD4 in gastric cancer indicated poor prognosis. ARV-825, a BRD4 inhibitor, could effectively suppress the growth and elevate the apoptosis of gastric cancer cells via transcription downregulation of c-MYC and PLK1. These results implied that ARV-825 could be a good therapeutic strategy to treat gastric cancer.https://www.frontiersin.org/articles/10.3389/fonc.2021.753119/fullARV-825BRD4gastric cancerc-MycPLK1 |
| spellingShingle | Xinmei Liao Xiaoqing Qian Xiaoqing Qian Zimu Zhang Yanfang Tao Zhiheng Li Qian Zhang Hui Liang Xiaolu Li Yi Xie Ran Zhuo Yanling Chen You Jiang Haibo Cao Jiaqi Niu Cuili Xue Jian Ni Jian Pan Daxiang Cui Daxiang Cui ARV-825 Demonstrates Antitumor Activity in Gastric Cancer via MYC-Targets and G2M-Checkpoint Signaling Pathways Frontiers in Oncology ARV-825 BRD4 gastric cancer c-Myc PLK1 |
| title | ARV-825 Demonstrates Antitumor Activity in Gastric Cancer via MYC-Targets and G2M-Checkpoint Signaling Pathways |
| title_full | ARV-825 Demonstrates Antitumor Activity in Gastric Cancer via MYC-Targets and G2M-Checkpoint Signaling Pathways |
| title_fullStr | ARV-825 Demonstrates Antitumor Activity in Gastric Cancer via MYC-Targets and G2M-Checkpoint Signaling Pathways |
| title_full_unstemmed | ARV-825 Demonstrates Antitumor Activity in Gastric Cancer via MYC-Targets and G2M-Checkpoint Signaling Pathways |
| title_short | ARV-825 Demonstrates Antitumor Activity in Gastric Cancer via MYC-Targets and G2M-Checkpoint Signaling Pathways |
| title_sort | arv 825 demonstrates antitumor activity in gastric cancer via myc targets and g2m checkpoint signaling pathways |
| topic | ARV-825 BRD4 gastric cancer c-Myc PLK1 |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2021.753119/full |
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