Chen Xihui, Wang Shiwen, Zhang Li, Yuan Shuying, Xu Tong, Zhu Feng, Zhang Yanmei, Jia Lijun
Cancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Department of Laboratory Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai, China.
Front Pharmacol. 2022 Jun 8;13:873166. doi: 10.3389/fphar.2022.873166. eCollection 2022.
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 and . 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.
食管鳞状细胞癌（ESCC）是全球最致命的消化系统癌症之一，缺乏有效的治疗策略。最近，人们发现天然产物雷公藤红素通过诱导细胞周期停滞和凋亡在几种人类癌症中发挥抗癌作用。然而，雷公藤红素是否以及如何抑制ESCC的肿瘤生长仍不清楚。在本研究中，我们首次证明雷公藤红素触发外源性和内源性凋亡途径以减少ESCC的肿瘤生长。机制研究表明，雷公藤红素通过ESCC细胞中ATF4的转录激活协同诱导DR5依赖性外源性凋亡和Noxa依赖性内源性凋亡。此外，我们发现FoxO3a-Bim途径参与了雷公藤红素诱导的ESCC细胞内源性凋亡。我们的研究阐明了雷公藤红素对ESCC的肿瘤抑制作用，并揭示了雷公藤红素诱导凋亡的先前未知机制，突出了雷公藤红素作为一种有前景的ESCC凋亡诱导治疗策略。
