Wang Jian, Lv Xiaoye, Guo Xiutian, Dong Yanbo, Peng Peipei, Huang Fang, Wang Peng, Zhang Haoqian, Zhou Jianguang, Wang Youliang, Wei Bo, Shang Zeng-Fu, Li Shanhu
Department of Cell Engineering, Beijing Institute of Biotechnology, 100850, Beijing, China.
Department of General Surgery, The General Hospital of People's Liberation Army, 100853, Beijing, China.
Oncogenesis. 2021 Jan 5;10(1):8. doi: 10.1038/s41389-020-00292-w.
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.
PI3K/AKT/mTOR信号通路在PTEN缺陷的癌细胞中持续激活，对其进行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受到限制。使用磷酸激酶阵列筛选了用PI3K/mTOR抑制剂BEZ235处理的PTEN缺陷癌细胞中的相关信号通路，并在用多种PI3K/AKT/mTOR抑制剂或敲低AKT后进一步验证。通过免疫组织化学分析胃癌患者组织芯片中PTEN表达水平与STAT3激酶磷酸化之间的相关性。对经过适当处理的PTEN缺陷癌细胞进行细胞增殖和克隆形成试验。进行细胞因子阵列、小分子抑制和敲低试验以鉴定相关因子。在用PI3K/AKT/mTOR和/或STAT3抑制剂处理的裸鼠中建立PTEN缺陷的肿瘤异种移植模型。PTEN缺陷与低STAT3活性呈正相关。PI3K/mTOR抑制剂增加巨噬细胞迁移抑制因子（MIF）的表达和分泌，并激活JAK1/STAT3信号通路。癌细胞和体内肿瘤异种移植模型均显示，联合抑制PI3K/AKT/mTOR和STAT3活性可增强BEZ235对PTEN缺陷癌细胞增殖的抑制作用。我们的研究结果为PTEN缺陷的癌症患者的新治疗策略提供了科学依据。
