Targeting mTOR suppressed colon cancer growth through 4EBP1/eIF4E/PUMA pathway.
Targeting mTOR suppressed colon cancer growth through 4EBP1/eIF4E/PUMA pathway.
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靶向 mTOR 通过 4EBP1/eIF4E/PUMA 通路抑制结肠癌生长。
DOI：
10.1038/s41417-019-0117-7
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发表时间：
2019
影响因子：
6.4
通讯作者：
Zhang Yingjie
中科院分区：
文献类型：
--
作者：
Wang Huanan;Liu Yeying;Ding Jie;Huang Yuan;Liu Jing;Liu Nannan;Ao Yue;Hong Yi;Wang Lefeng;Zhang Lingling;Wang Jiangang;Zhang Yingjie
结直肠癌是男性和女性中第三常见的恶性肿瘤，死亡率增加，但预后不佳。靶向mTOR成为一种有效的方法，在包括结肠癌在内的多种癌症中显示出良好的抗肿瘤活性。然而，抗结肠癌的潜在机制仍不完全清楚。在这里，我们证明了AZD8055和OSI-027的抗癌作用至少部分是通过细胞凋亡启动的渐进过程来调节的，该过程从mTOR抑制、4EBP1去磷酸化或EZH2抑制，从而通过内在的线粒体途径导致PUMA依赖的细胞凋亡。此外，AZD8055还能显著抑制小鼠结直肠癌的生长。PUMA缺失导致对双重mTOR抑制剂产生耐药性，提示PUMA介导了体内和体外的致癌作用。总而言之，这些发现确立了PUMA在推动AZD8055和OSI-027靶向mTOR抗肿瘤疗效方面的重要地位，并为当前的临床评估提供了理论基础。
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.