文章：

靶向mTOR通过4EBP1/eIF4E/PUMA途径抑制结肠癌生长

Targeting mTOR suppressed colon cancer growth through 4EBP1/eIF4E/PUMA pathway 

原文发布日期：2019-07-01 

英文摘要：

Colorectal cancer is the third most frequently diagnosed malignancies among both men and women, which has an increased mortality but a poor prognosis. Targeting mTOR becomes an effective approach that shows promising antitumor activities in various cancers including colonic carcinoma. However, the potential mechanism against colon cancer remains incompletely understood. Here, we demonstrated that the anti-cancer effect of AZD8055 and OSI-027 is at least in part modulated by the gradual process of apoptosis initiation, progressing from mTOR suppression, 4EBP1 dephosphorylation, or EZH2 suppression, thereby leading to PUMA-dependent apoptosis via the intrinsic mitochondrial pathway. Furthermore, AZD8055 inhibited colorectal cancer tumor growth in mice significantly. PUMA deletion caused resistance of dual mTOR inhibitors, suggesting PUMA mediated carcinogenesis in vitro and in vivo. Collectively, these findings established a vital status of PUMA in driving the antineoplastic efficacy of targeting mTOR by AZD8055 and OSI-027 and offered the rationales for the current clinical assessment. 

摘要翻译： 

结直肠癌是男性和女性中第三大高发恶性肿瘤，其死亡率呈上升趋势但预后较差。靶向mTOR已成为一种有效的治疗策略，在包括结肠癌在内的多种癌症中展现出良好的抗肿瘤活性。然而，其对结肠癌的潜在作用机制尚未完全阐明。本研究证实，AZD8055和OSI-027的抗癌效应至少部分通过逐步诱导凋亡进程实现——从mTOR抑制、4EBP1去磷酸化或EZH2抑制开始，最终通过内在线粒体途径引发PUMA依赖性细胞凋亡。此外，AZD8055能显著抑制小鼠结直肠癌肿瘤生长。PUMA基因缺失会导致双mTOR抑制剂产生耐药性，表明PUMA在体外和体内均介导致癌过程。综上所述，这些研究发现确立了PUMA在AZD8055和OSI-027靶向mTOR抗肿瘤疗效中的关键地位，并为当前临床评估提供了理论依据。

原文链接：

Targeting mTOR suppressed colon cancer growth through 4EBP1/eIF4E/PUMA pathway