Simultaneous targeting PI3K and PERK pathways promotes cell death and improves the clinical prognosis in esophageal squamous carcinoma.
Simultaneous targeting PI3K and PERK pathways promotes cell death and improves the clinical prognosis in esophageal squamous carcinoma.
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同时靶向 PI3K 和 PERK 通路可促进细胞死亡并改善食管鳞癌的临床预后。
DOI：
10.1016/j.bbrc.2017.08.156
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发表时间：
2017-11
期刊：
影响因子：
--
通讯作者：
Xie Cong-Hua
中科院分区：
文献类型：
--
作者：
Wang Shao-Qi;Wang Xiao;Zheng Kai;Liu Kai-Sheng;Wang Shao-Xiang;Xie Cong-Hua
PI3K通路是一个重要的抗肿瘤靶点，但其在食管鳞状细胞癌（ESCC）中的作用和机制尚不清楚。通过对癌症基因组图谱（Cancer Genome Atlas， TCGA）数据集的分析，我们发现pi3k水平在人类食管癌组织中与非癌组织相比显著上调。PI3K的改变可以显著影响ESCC患者的总体生存，但在食管腺癌（EAC）中没有影响。我们发现经典的PI3K抑制剂LY294002明显抑制雷帕霉素（mTOR）途径的典型哺乳动物靶点，抑制ESCC的生长，对正常细胞的毒性较小。此外，LY294002还抑制非典型的pkr样ER激酶(PERK)/elF2α/ATF4通路。siRNA和PERK/elF2α/ATF4通路小分子抑制剂GSK2656157均能显著抑制ESCC的生长。更重要的是，GSK2656157加重了LY294002对ESCC细胞生长、集落形成和诱导凋亡的抑制作用。此外，在ESCC患者中，PI3K和PERK通路双高表达，与单独使用PI3K相比，总生存期（OS）的差异更显著。上述结果提示，双靶向PI3K和PERK通路可能改善ESCC患者的临床预后，提高治疗效果。
PI3K pathway is an important anti-tumor target, but its effect and mechanism is not clear in esophageal squamous cell carcinoma (ESCC). By analysis of the Cancer Genome Atlas (TCGA) datasets, we found that PI3Ks level were significantly upregulated in human esophageal cancer tissues compared with that in non-cancer tissues. The alteration of PI3K can significantly affect the overall patient survival in ESCC but not in esophageal adenocarcinoma (EAC). We found that the classic PI3K inhibitor LY294002 obviously inhibited the canonical mammalian target of rapamycin (mTOR) pathway and restrained the growth of ESCC with less toxicity to normal cells. Besides, LY294002 inhibited noncanonical PKR-like ER kinase (PERK)/elF2α/ATF4 pathway as well. Both siRNA and the small molecule inhibitor GSK2656157 against PERK/elF2α/ATF4 pathway can significantly inhibit the growth of ESCC. More importantly, GSK2656157 aggravated the inhibitory effect of LY294002 on cell growth, colony formation, and apoptosis induction of ESCC. In addition of dual high expression of PI3K and PERK pathways in the ESCC patients, the difference of overall survival (OS) was more significant than using PI3K alone. These results indicated that dual targeting of PI3K and PERK pathways might improve clinical prognosis and enhance the treatment of ESCC patients.
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影响因子：
--
作者：
Rogers HA;Estranero J;Gudka K;Grundy RG
通讯作者：
Grundy RG
影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
64.8
作者：
Cancer Genome Atlas Research Network;Analysis Working Group: Asan University;BC Cancer Agency;Brigham and Women’s Hospital;Broad Institute;Brown University;Case Western Reserve University;Dana-Farber Cancer Institute;Duke University;Greater Poland Cancer Centre;Harvard Medical School;Institute for Systems Biology;KU Leuven;Mayo Clinic;Memorial Sloan Kettering Cancer Center;National Cancer Institute;Nationwide Children’s Hospital;Stanford University;University of Alabama;University of Michigan;University of North Carolina;University of Pittsburgh;University of Rochester;University of Southern California;University of Texas MD Anderson Cancer Center;University of Washington;Van Andel Research Institute;Vanderbilt University;Washington University;Genome Sequencing Center: Broad Institute;Washington University in St. Louis;Genome Characterization Centers: BC Cancer Agency;Broad Institute;Harvard Medical School;Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University;University of North Carolina;University of Southern California Epigenome Center;University of Texas MD Anderson Cancer Center;Van Andel Research Institute;Genome Data Analysis Centers: Broad Institute;Brown University:;Harvard Medical School;Institute for Systems Biology;Memorial Sloan Kettering Cancer Center;University of California Santa Cruz;University of Texas MD Anderson Cancer Center;Biospecimen Core Resource: International Genomics Consortium;Research Institute at Nationwide Children’s Hospital;Tissue Source Sites: Analytic Biologic Services;Asan Medical Center;Asterand Bioscience;Barretos Cancer Hospital;BioreclamationIVT;Botkin Municipal Clinic;Chonnam National University Medical School;Christiana Care Health System;Cureline;Duke University;Emory University;Erasmus University;Indiana University School of Medicine;Institute of Oncology of Moldova;International Genomics Consortium;Invidumed;Israelitisches Krankenhaus Hamburg;Keimyung University School of Medicine;Memorial Sloan Kettering Cancer Center;National Cancer Center Goyang;Ontario Tumour Bank;Peter MacCallum Cancer Centre;Pusan National University Medical School;Ribeirão Preto Medical School;St. Joseph’s Hospital &Medical Center;St. Petersburg Academic University;Tayside Tissue Bank;University of Dundee;University of Kansas Medical Center;University of Michigan;University of North Carolina at Chapel Hill;University of Pittsburgh School of Medicine;University of Texas MD Anderson Cancer Center;Disease Working Group: Duke University;Memorial Sloan Kettering Cancer Center;National Cancer Institute;University of Texas MD Anderson Cancer Center;Yonsei University College of Medicine;Data Coordination Center: CSRA Inc.;Project Team: National Institutes of Health
通讯作者：
Project Team: National Institutes of Health
影响因子：
--
作者：
Cai Y;Dodhia S;Su GH
通讯作者：
Su GH
影响因子：
30.5
作者：
Fukao, T;Tanabe, M;Koyasu, S
通讯作者：
Koyasu, S