Cooperative interaction between protein inhibitor of activated signal transducer and activator of transcription-3 with epidermal growth factor receptor blockade in lung cancer.
Cooperative interaction between protein inhibitor of activated signal transducer and activator of transcription-3 with epidermal growth factor receptor blockade in lung cancer.
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DOI：
10.1002/ijc.24553
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发表时间：
2009-10-01
影响因子：
6.4
通讯作者：
Dowlati A
中科院分区：
文献类型：
--
作者：
Kluge A;Dabir S;Kern J;Nethery D;Halmos B;Ma P;Dowlati A
表皮生长因子受体（EGFR）靶向治疗非小细胞肺癌（NSCLC）是一种既定的治疗方式，但仅使少数患者受益。STAT 3（signal transducer and activator of transcription-3）在非小细胞肺癌的致癌信号转导通路中起重要作用。STAT 3的抑制导致NSCLC生长抑制和细胞凋亡。我们之前已经表明，与单独阻断EGFR相比，小分子对EGFR和STAT 3的联合抑制导致治疗功效的改善。然而，STAT 3蛋白具有许多内源性负调节因子，包括PIAS 3（活化的STAT 3的蛋白质抑制剂）。在这项研究中，我们首次研究了PIAS 3在调节肺癌致癌EGFR-STAT 3信号通路中的作用，以及PIAS 3与EGFR阻断剂联合使用在NSCLC中的抗增殖作用。我们证明PIAS 3在所有NSCLC细胞中以不同程度表达。EGF和IL-6刺激导致PIAS 3与STAT 3的关联。PIAS 3/STAT 3复合物然后结合STAT 3 DNA结合序列，导致STAT 3调节基因表达。使用PIAS 3表达构建体，PIAS 3的过表达降低了STAT 3转录活性。此外，PIAS 3的过表达持续降低增殖。EGFR阻断和PIAS 3过表达的组合与单独的EGFR阻断或PIAS 3过表达相比具有显著更大的抗增殖作用。总之，PIAS 3在NSCLC细胞系中表达，并且其过表达降低了STAT 3转录活性，降低了NSCLC细胞的增殖，并且当与EGFR抑制剂联合使用时，增加了抗增殖作用。
Epidermal Growth Factor Receptor (EGFR) targeting in non-small cell lung cancer (NSCLC) is an established treatment modality, yet only benefits a minority of patients. STAT3 (signal transducer and activator of transcription-3) plays an important role in the oncogenic signal transduction pathway of NSCLC. Inhibition of STAT3 results in NSCLC growth inhibition and apoptosis. We have previously shown that combined inhibition of EGFR and STAT3 by small molecules resulted in improved therapeutic efficacy as compared to blocking EGFR alone. However, the STAT3 protein has a number of endogenous negative regulators including PIAS3 (Protein Inhibitor of Activated STAT3). In this study we investigated for the first time the role of PIAS3 in modulating oncogenic EGFR-STAT3 signaling pathway in lung cancer and the antiproliferative effect of using PIAS3 in conjunction with EGFR blockade in NSCLC. We demonstrate that PIAS3 is expressed in variable degrees in all NSCLC cells. EGF and IL-6 stimulation resulted in the association of PIAS3 with STAT3. The PIAS3/STAT3 complex then bound the STAT3 DNA binding sequence resulting in STAT3 regulated gene expression. Over-expression of PIAS3, using a PIAS3 expression construct, decreases STAT3 transcriptional activity. Furthermore, over-expression of PIAS3 consistently decreased proliferation. EGFR blockade and PIAS3 over-expression in combination had significantly greater anti-proliferative effects as compared to either EGFR blockade or PIAS3 over-expression alone. In conclusion, PIAS3 is expressed in NSCLC cell lines and its over-expression decreased STAT3 transcriptional activity, decreased proliferation of NSCLC cells and when used in conjunction with EGFR inhibitors, increased the anti-proliferative effects.
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DOI：
10.1016/j.bbrc.2003.12.054
发表时间：
2004-01-30
影响因子：
3.1
作者：
Nojiri, S;Joh, T;Ito, M
通讯作者：
Ito, M
影响因子：
8
作者：
Gross, M;Liu, B;Shuai, K
通讯作者：
Shuai, K
影响因子：
158.5
作者：
Shepherd, FA;Pereira, JR;Seymour, L
通讯作者：
Seymour, L
影响因子：
4.3
作者：
Inghirami, G;Chiarle, R;Levy, DE
通讯作者：
Levy, DE
影响因子：
254.7
作者：
Jemal, A;Murray, T;Thun, MJ
通讯作者：
Thun, MJ