Feedback activation of STAT3 limits the response to PI3K/AKT/mTOR inhibitors in PTEN-deficient cancer cells.
Feedback activation of STAT3 limits the response to PI3K/AKT/mTOR inhibitors in PTEN-deficient cancer cells.
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STAT3 的反馈激活限制了 PTEN 缺陷癌细胞对 PI3K/AKT/mTOR 抑制剂的反应。
DOI：
10.1038/s41389-020-00292-w
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发表时间：
2021-01-05
期刊：
影响因子：
6.2
通讯作者：
Li S
中科院分区：
文献类型：
--
作者：
Wang J;Lv X;Guo X;Dong Y;Peng P;Huang F;Wang P;Zhang H;Zhou J;Wang Y;Wei B;Shang ZF;Li S
PI3K/AKT/mTOR信号通路在PTEN缺失的癌细胞中具有结构性活性，其靶向抑制具有显著的抗肿瘤作用。然而，由于耐药性，靶向治疗的疗效往往是有限的。PI3K/mTOR抑制剂BEZ235处理的PTEN缺陷癌细胞中的相关信号通路被用磷酸激酶阵列筛选，并在多个PI3K/AKT/mTOR抑制剂或AKT被敲除处理后进一步验证。用免疫组织化学方法分析PTEN在胃癌组织芯片中的表达水平与STAT3激酶磷酸化的相关性。对经过适当处理的PTEN缺陷癌细胞进行了细胞增殖和克隆形成实验。通过细胞因子阵列、小分子抑制实验和基因敲除实验确定相关因素。用PI3K/AKT/mTOR和/或STAT3抑制剂处理裸鼠，建立PTEN缺陷性肿瘤移植瘤模型。PTEN缺乏与STAT3活性低下呈正相关。PI3K/mTOR抑制剂增加巨噬细胞移动抑制因子(MIF)的表达和分泌，激活JAK1/STAT3信号通路。癌细胞和体内移植瘤均表明，PI3K/AKT/mTOR和STAT3活性的联合抑制增强了BEZ235对PTEN缺陷性癌细胞增殖的抑制作用。我们的发现为PTEN缺乏症癌症患者的新治疗策略提供了科学依据。
The PI3K/AKT/mTOR signaling pathway is constitutively active in PTEN-deficient cancer cells, and its targeted inhibition has significant anti-tumor effects. However, the efficacy of targeted therapies is often limited due to drug resistance. The relevant signaling pathways in PTEN-deficient cancer cells treated with the PI3K/mTOR inhibitor BEZ235 were screened using a phosphokinase array, and further validated following treatment with multiple PI3K/AKT/mTOR inhibitors or AKT knockdown. The correlation between PTEN expression levels and STAT3 kinase phosphorylation in the tissue microarrays of gastric cancer patients was analyzed by immunohistochemistry. Cell proliferation and clonogenic assays were performed on the suitably treated PTEN-deficient cancer cells. Cytokine arrays, small molecule inhibition and knockdown assays were performed to identify related factors. PTEN-deficient tumor xenografts were established in nude mice that were treated with PI3K/AKT/mTOR and/or STAT3 inhibitors. PTEN deficiency was positively correlated with low STAT3 activity. PI3K/mTOR inhibitors increased the expression and secretion of macrophage migration inhibitory factor (MIF) and activated the JAK1/STAT3 signaling pathway. Both cancer cells and in vivo tumor xenografts showed that the combined inhibition of PI3K/AKT/mTOR and STAT3 activity enhanced the inhibitory effect of BEZ235 on the proliferation of PTEN-deficient cancer cells. Our findings provide a scientific basis for a novel treatment strategy in cancer patients with PTEN deficiency.
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影响因子：
28.2
作者：
Ni J;Liu Q;Xie S;Carlson C;Von T;Vogel K;Riddle S;Benes C;Eck M;Roberts T;Gray N;Zhao J
通讯作者：
Zhao J
影响因子：
6.6
作者：
Cheon SK;Kim HP;Park YL;Jang JE;Lim Y;Song SH;Han SW;Kim TY
通讯作者：
Kim TY
DOI：
10.1073/pnas.171060098
发表时间：
2001-08-28
影响因子：
11.1
作者：
Podsypanina, K;Lee, RT;Parsons, R
通讯作者：
Parsons, R
影响因子：
50.3
作者：
Mulholland DJ;Tran LM;Li Y;Cai H;Morim A;Wang S;Plaisier S;Garraway IP;Huang J;Graeber TG;Wu H
通讯作者：
Wu H
影响因子：
8
作者：
Real, PJ;Sierra, A;Fernandez-Luna, JL
通讯作者：
Fernandez-Luna, JL