文献

J-GLOBAL ID：202002228357650507   整理番号：20A0215205

Protac分子によるbet蛋白質の標的化はHCC細胞における強力な抗癌活性を誘発する【JST・京大機械翻訳】

Targeting BET Proteins With a PROTAC Molecule Elicits Potent Anticancer Activity in HCC Cells

著者 (54件)： Zhang Huapeng (Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China) ,  Zhang Huapeng (Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China) ,  Zhang Huapeng (Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Zhengzhou, China) ,  Zhang Huapeng (Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, China) ,  Li Gongquan (Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China) ,  Li Gongquan (Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China) ,  Li Gongquan (Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Zhengzhou, China) ,  Li Gongquan (Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, China) ,  Zhang Yi (Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China) ,  Zhang Yi (Department of Orthopaedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China) ,  Shi Jihua (Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China) ,  Shi Jihua (Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China) ,  Shi Jihua (Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Zhengzhou, China) ,  Shi Jihua (Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, China) ,  Yan Bing (Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China) ,  Yan Bing (Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China) ,  Yan Bing (Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Zhengzhou, China) ,  Yan Bing (Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, China) ,  Tang Hongwei (Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China) ,  Tang Hongwei (Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China) ,  Tang Hongwei (Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Zhengzhou, China) ,  Tang Hongwei (Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, China) ,  Chen Sanyang (Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China) ,  Chen Sanyang (Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China) ,  Chen Sanyang (Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Zhengzhou, China) ,  Chen Sanyang (Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, China) ,  Zhang Jiakai (Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China) ,  Zhang Jiakai (Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China) ,  Zhang Jiakai (Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Zhengzhou, China) ,  Zhang Jiakai (Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, China) ,  Wen Peihao (Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China) ,  Wen Peihao (Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China) ,  Wen Peihao (Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Zhengzhou, China) ,  Wen Peihao (Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, China) ,  Wang Zhihui (Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China) ,  Wang Zhihui (Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China) ,  Wang Zhihui (Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Zhengzhou, China) ,  Wang Zhihui (Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, China) ,  Pang Chun (Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China) ,  Pang Chun (Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China) ,  Pang Chun (Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Zhengzhou, China) ,  Pang Chun (Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, China) ,  Li Jie (Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China) ,  Li Jie (Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China) ,  Li Jie (Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Zhengzhou, China) ,  Li Jie (Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, China) ,  Guo Wenzhi (Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China) ,  Guo Wenzhi (Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China) ,  Guo Wenzhi (Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Zhengzhou, China) ,  Guo Wenzhi (Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, China) ,  Zhang Shuijun (Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China) ,  Zhang Shuijun (Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China) ,  Zhang Shuijun (Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, Zhengzhou, China) ,  Zhang Shuijun (Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, China)
資料名： Frontiers in Oncology (Web)  (Frontiers in Oncology (Web))
巻： 9  ページ： 1471  発行年： 2019年 
JST資料番号： U7089A  ISSN： 2234-943X  資料種別： 逐次刊行物 (A)
記事区分： 原著論文  発行国： スイス (CHE)  言語： 英語 (EN)

抄録/ポイント： 背景と目的:ブロモドメインと末端ドメイン(BET)ファミリー蛋白質は,ヒト悪性腫瘍に関与する後成的調節因子である。蛋白質分解標的キメラ(PROTAC)を用いた分解のためのBET蛋白質の標的化は,最近,癌治療の分野で注目を集めている。BET蛋白質は,HCC細胞および腫瘍組織で過剰発現することが見出されている。しかし,肝細胞癌(HCC)におけるBET-PROTACsの生物学的活性は不明のままである。本研究では,in vitroおよびin vivoモデルを用いてBET-PROTAC分子,BETd-260の抗HCC活性を検討した。【方法】BETd-260媒介抗HCC活性を,細胞生存率,アポトーシス分析によって研究した。マウスにおいて細胞系由来HCC異種移植モデルを用いて有効性を調べた。RT-PCR,ウエスタンブロット法および免疫組織化学的染色によって,抗癌機構を調査した。【結果】BETd-260は,HCC細胞において細胞生存率を強く抑制し,アポトーシスを強力に誘導した。BETd-260は,HCC細胞におけるいくつかのアポトーシス遺伝子の発現を相反的に調節した。すなわち,アポトーシス(XIAP)の抗アポトーシスMcl-1,Bcl-2,c-Myc,およびX連鎖阻害剤の発現を抑制し,一方,プロアポトーシスBadの発現を増加させる。BETd-260処理は,ミトコンドリア膜完全性の破壊をもたらし,HCC細胞における内因性シグナル伝達を介してアポトーシスを誘発した。BETd-260はHCC異種移植組織においてアポトーシスを誘発し,マウスにおけるHCC異種移植腫瘍の増殖を大きく阻害した。結論:著者らのデータは,分解のためのBETの薬理学的標的化がHCCの治療のための新しい治療戦略である可能性があることを示唆する。Copyright 2020 The Author(s) All rights reserved. Translated from English into Japanese by JST.【JST・京大機械翻訳】

シソーラス用語： タンパク質分解 ,  肝細胞癌 ,  遺伝子 ,  *ターゲティング ,  薬理学 ,  ウェスタンブロット法 ,  異種移植 ,  ヒト ,  in vitro実験 ,  アポトーシス ,  治療計画 ,  *抗腫瘍作用 ,  生物活性 ,  キメラ ,  *タンパク質

著者キーワード (5件)： BET ,  Protac ,  蛋白質分解 ,  HCC ,  アポトーシス

分類 (1件)： 腫ようの化学・生化学・病理学  (GE02030N)

引用文献 (33件)：

• Villanueva A, Minguez B, Forner A, Reig M, Llovet JM. Hepatocellular carcinoma: novel molecular approaches for diagnosis, prognosis, and therapy. Ann Rev Med. (2010) 61:317-28. doi: 10.1146/annurev.med.080608.100623
• Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. (2017) 389:56-66. doi: 10.1016/S0140-6736(16)32453-9
• Mertz JA, Conery AR, Bryant BM, Sandy P, Balasubramanian S, Mele DA, et al. Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proc Natl Acad Sci USA. (2011) 108:16669-74. doi: 10.1073/pnas.1108190108
• French CA, Miyoshi I, Kubonishi I, Grier HE, Perez-Atayde AR, Fletcher JA. BRD4-NUT fusion oncogene: a novel mechanism in aggressive carcinoma. Cancer Res. (2003) 63:304-7. doi: 10.1073/pnas.1108190108
• Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith WB, Fedorov O, et al. Selective inhibition of BET bromodomains. Nature. (2010) 468:1067. doi: 10.1038/nature09504

タイトルに関連する用語 (8件)： PROTAC ,  分子 ,  蛋白質 ,  標的化 ,  HCC ,  細胞 ,  抗癌活性 ,  誘発