Celastrol Inhibited Human Esophageal Cancer by Activating DR5-Dependent Extrinsic and Noxa/Bim-Dependent Intrinsic Apoptosis.
Celastrol Inhibited Human Esophageal Cancer by Activating DR5-Dependent Extrinsic and Noxa/Bim-Dependent Intrinsic Apoptosis.
复制标题
雷公藤红素通过激活 DR5 依赖性外源性和 Noxa/Bim 依赖性内源性细胞凋亡抑制人食管癌
DOI：
10.3389/fphar.2022.873166
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发表时间：
2022
影响因子：
5.6
通讯作者：
Jia, Lijun
中科院分区：
文献类型：
--
作者：
Chen, Xihui;Wang, Shiwen;Zhang, Li;Yuan, Shuying;Xu, Tong;Zhu, Feng;Zhang, Yanmei;Jia, Lijun
关键词：
食管鳞状细胞癌（ESCC）是世界上最致命的消化系统癌症之一，缺乏有效的治疗策略。近年来，研究发现天然产物雷公藤红素通过诱导细胞周期阻滞和细胞凋亡对多种人类癌症发挥抗癌作用。然而，雷公藤红素是否以及如何抑制ESCC的肿瘤生长仍然是难以捉摸的。在本研究中，我们第一次证明雷公藤红素在体内和体外同时触发了外源性和内源性凋亡途径，从而减少了ESCC的肿瘤生长。机制研究表明雷公藤红素通过转录激活ATF 4协同诱导ESCC细胞DR 5依赖的外源性凋亡和Noxa依赖的内源性凋亡。此外，我们发现FoxO 3a-Bim通路参与雷公藤红素诱导的ESCC细胞的内源性凋亡。我们的研究阐明了雷公藤红素对ESCC的肿瘤抑制功效，并揭示了雷公藤红素诱导细胞凋亡的一种先前未知的机制，突出了雷公藤红素作为一种有前途的诱导细胞凋亡的ESCC治疗策略。
Esophageal squamous cell carcinoma (ESCC) is one of the deadliest digestive system cancers worldwide lacking effective therapeutic strategies. Recently, it has been found that the natural product celastrol plays an anti-cancer role in several human cancers by inducing cell cycle arrest and apoptosis. However, it remains elusive whether and how celastrol suppresses tumor growth of ESCC. In the present study, for the first time, we demonstrated that celastrol triggered both extrinsic and intrinsic apoptosis pathways to diminish the tumor growth of ESCC in vivo and in vitro. Mechanistic studies revealed that celastrol coordinatively induced DR5-dependent extrinsic apoptosis and Noxa-dependent intrinsic apoptosis through transcriptional activation of ATF4 in ESCC cells. Furthermore, we found that the FoxO3a-Bim pathway was involved in the intrinsic apoptosis of ESCC cells induced by celastrol. Our study elucidated the tumor-suppressive efficacy of celastrol on ESCC and revealed a previously unknown mechanism underlying celastrol-induced apoptosis, highlighting celastrol as a promising apoptosis-inducing therapeutic strategy for ESCC.
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DOI：
10.3390/molecules26040933
发表时间：
2021-02-10
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Ma L;Zhang M;Zhao R;Wang D;Ma Y;Li A
通讯作者：
Li A
影响因子：
12.4
作者：
Kale J;Osterlund EJ;Andrews DW
通讯作者：
Andrews DW
Neddylation 抑制通过 ATF4-CHOP-DR5 轴激活人食管癌细胞的外源性凋亡途径
影响因子：
11.5
作者：
Chen, Ping;Hu, Tao;Jia, Lijun
通讯作者：
Jia, Lijun
影响因子：
12.4
作者：
Shats, Igor;Deng, Michael;You, Lingchong
通讯作者：
You, Lingchong
影响因子：
4.3
作者：
Thu, K. L.;Soria-Bretones, I.;Cescon, D. W.
通讯作者：
Cescon, D. W.