Inhibition of the AKT/mTOR pathway negatively regulates PTEN expression via miRNAs.
Inhibition of the AKT/mTOR pathway negatively regulates PTEN expression via miRNAs.
复制标题
抑制 AKT/mTOR 通路可通过 miRNA 负向调节 PTEN 表达
DOI：
10.3724/abbs.2022159
复制
发表时间：
2022-10-25
影响因子：
3.7
通讯作者：
Zhang H
中科院分区：
文献类型：
--
作者：
Wan L;Wang Y;Li J;Wang Y;Zhang H
PI 3 K/AKT/mTOR通路在肿瘤的发生发展中起重要作用，而PTEN在PI 3 K/AKT/mTOR通路中的负调控作用已为人们所熟知，但PTEN是否能被PI 3 K/AKT/mTOR负调控尚未见报道。在这里，我们的目的是调查之间的潜在调控关系PTEN和Akt/mTOR抑制MEFs。用AKT抑制剂MK 2206和mTOR抑制剂雷帕霉素和Torin 2处理AKT 1 E17 K和TSC 2-/-MEF。真实的时间PCR、核质分离和免疫荧光分析结果显示，抑制AKT或mTOR可抑制PTEN在AKT 1 E17 K和TSC 2-/- MEFs中的表达，但对PTEN的转录、亚细胞定位、eIF 4 E依赖的翻译起始、溶酶体和蛋白酶体介导的降解无明显影响。此外，mTOR抑制导致小鼠PTEN-3′ UTR结合的miRNA（包括miR-23 a-3 p、miR-23 b-3 p、miR-25- 3 p和miR-26 a-5 p）增加，如双荧光素酶报告基因测定和miRNA阵列分析所示，并且miRNA抑制剂协同挽救PTEN水平的下降。总的来说，我们的研究结果证实了mTOR的抑制通过上调miRNA抑制PTEN表达，为mTOR抑制剂在治疗mTOR激活相关肿瘤中的有限功效提供了新的解释，并表明mTOR和miRNA的双重抑制是克服mTOR相关癌症治疗抗性的有希望的治疗策略。
PI3K/AKT/mTOR pathway plays important roles in cancer development, and the negative role of PTEN in the PI3K/AKT/mTOR pathway is well known, but whether PTEN can be inversely regulated by PI3K/AKT/mTOR has rarely been reported. Here we aim to investigate the potential regulatory relationship between PTEN and Akt/mTOR inhibition in MEFs. AKT1 E17K and TSC2 –/– MEFs were treated with the AKT inhibitor MK2206 and the mTOR inhibitors rapamycin and Torin2. Our results reveal that inhibition of AKT or mTOR suppresses PTEN expression in AKT1 E17K and TSC2 –/– MEFs, but the transcription, subcellular localization, eIF4E-dependent translational initiation or lysosome- and proteasome-mediated degradation of PTEN change little, as shown by the real time PCR, nucleus cytoplasm separation assay and immunofluorescence analysis. Moreover, mTOR suppression leads to augmentation of mouse PTEN-3′UTR-binding miRNAs, including miR-23a-3p, miR-23b-3p, miR-25-3p and miR-26a-5p, as shown by the dual luciferase reporter assay and miRNA array analysis, and miRNA inhibitors collaborately rescue the decline of PTEN level. Collectively, our findings confirm that inhibition of mTOR suppresses PTEN expression by upregulating miRNAs, provide a novel explanation for the limited efficacy of mTOR inhibitors in the treatment of mTOR activation-related tumors, and indicate that dual inhibition of mTOR and miRNA is a promising therapeutic strategy to overcome the resistance of mTOR-related cancer treatment.
登录
查看更多内容
DOI：
10.1056/nejmoa1914919
发表时间：
2020-05-28
期刊：
The New England journal of medicine
影响因子：
--
作者：
Lee YR;Yehia L;Kishikawa T;Ni Y;Leach B;Zhang J;Panch N;Liu J;Wei W;Eng C;Pandolfi PP
通讯作者：
Pandolfi PP
影响因子：
5.4
作者：
Kotelevets, Larissa;Trifault, Barbara;Scott, Mark G. H.
通讯作者：
Scott, Mark G. H.
FBXO22 降解核 PTEN 促进肿瘤发生
影响因子：
16.6
作者：
Ge, Meng-Kai;Zhang, Na;Shen, Shao-Ming
通讯作者：
Shen, Shao-Ming
影响因子：
16
作者：
Bohm, Raphael;Imseng, Stefan;Hiller, Sebastian
通讯作者：
Hiller, Sebastian
DOI：
10.1158/1078-0432.ccr-20-2878
发表时间：
2021-03-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
通讯作者：
--