Hexokinase 2-mediated Warburg effect is required for PTEN- and p53-deficiency-driven prostate cancer growth.
Hexokinase 2-mediated Warburg effect is required for PTEN- and p53-deficiency-driven prostate cancer growth.
复制标题
DOI：
10.1016/j.celrep.2014.07.053
复制
发表时间：
2014-09-11
期刊：
影响因子：
8.8
通讯作者：
Deng Y
中科院分区：
文献类型：
--
作者：
Wang L;Xiong H;Wu F;Zhang Y;Wang J;Zhao L;Guo X;Chang LJ;Zhang Y;You MJ;Koochekpour S;Saleem M;Huang H;Lu J;Deng Y
越来越多的证据表明，肿瘤抑制基因Pten和p53的共缺失在体内去势抵抗性前列腺癌的发展中起着至关重要的作用。然而，Pten/p53缺陷驱动前列腺肿瘤发生的分子机制仍不完全清楚。基于我们对Pten/p53缺陷型小鼠胚胎成纤维细胞（MEFs）的研究，我们在这里报告了前列腺癌细胞中Pten和p53的联合缺失选择性上调己糖激酶2（HK 2）。从机制上讲，Pten缺失通过激活AKT-mTORC 1 - 4 EBP 1轴增加HK 2 mRNA翻译，p53缺失通过抑制miR 143生物合成增强HK 2 mRNA稳定性。遗传研究表明，HK 2介导的有氧糖酵解，称为瓦尔堡效应，是前列腺癌异种移植小鼠模型中Pten/p53缺陷驱动的肿瘤生长所必需的。我们的研究结果表明，HK 2可能是携带Pten和p53突变的前列腺癌患者的治疗靶点。
Accumulating evidence suggests that co-deletion of tumor suppressor genes Pten and p53 plays a crucial role in the development of castration-resistant prostate cancer in vivo. However, the molecular mechanism underlying Pten/p53-deficiency driven prostate tumorigenesis remains incompletely understood. Building upon insights gained from our studies with Pten/p53-deficient mouse embryonic fibroblasts (MEFs), we report here that hexokinase 2 (HK2) is selectively upregulated by the combined loss of Pten and p53 in prostate cancer cells. Mechanistically, Pten deletion increases HK2 mRNA translation through activation of the AKT-mTORC1-4EBP1 axis and p53 loss enhances HK2 mRNA stability through inhibition of miR143 biogenesis. Genetic studies demonstrate that HK2-mediated aerobic glycolysis, known as the Warburg effect, is required for Pten/p53-deficiency driven tumor growth in xenograft mouse models of prostate cancer. Our findings suggest that HK2 might be a therapeutic target for prostate cancer patients carrying Pten and p53 mutations.
登录
查看更多内容
影响因子：
64.5
作者：
Jacinto, Estela;Facchinetti, Valeria;Su, Bing
通讯作者：
Su, Bing
MicroRNA-143 (miR-143) 通过靶向己糖激酶 2 基因调节癌症糖酵解
影响因子：
4.8
作者：
Fang, Rong;Xiao, Tian;Ji, Hongbin
通讯作者：
Ji, Hongbin
影响因子：
10.5
作者：
Chen, Mei-Ling;Xu, Pei-Zhang;Hay, Nissim
通讯作者：
Hay, Nissim
影响因子：
30.8
作者：
Jonkers, J;Meuwissen, R;Berns, A
通讯作者：
Berns, A
影响因子：
64.5
作者：
Fang, Min;Shen, Zhirong;Wang, Xiaodong
通讯作者：
Wang, Xiaodong