Sugiol inhibits STAT3 activity via regulation of transketolase and ROS-mediated ERK activation in DU145 prostate carcinoma cells
Sugiol inhibits STAT3 activity via regulation of transketolase and ROS-mediated ERK activation in DU145 prostate carcinoma cells
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DOI：
10.1016/j.bcp.2015.06.033
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发表时间：
2015-09-01
影响因子：
5.8
通讯作者：
Kwon, Byoung-Mog
中科院分区：
文献类型：
--
作者：
Jung, Seung-Nam;Shin, Dae-Seop;Kwon, Byoung-Mog
信号转导子和转录激活子3（STAT 3）在多种人类癌症中被组成性激活，并且已被用作肿瘤的治疗靶点。本研究使用依赖于STAT 3的荧光素酶报告系统筛选天然产物以鉴定抑制STAT 3活性的化合物。杉醇被鉴定为以剂量依赖性方式降低荧光素酶活性的化合物。Sugiol特异性抑制DU 145前列腺细胞中STAT 3在Tyr-705处的磷酸化，并且这种抑制不依赖于STAT 3上游激酶。Sugiol诱导细胞周期停滞，并降低STAT 3靶基因的表达水平，如cyclin D1，cyclin A和survivin。值得注意的是，我们观察到sugiol与转酮醇酶（一种中枢代谢酶）相互作用，并增加ROS水平，导致ERR激活，从而抑制STAT 3活性。蛋白磷酸酶MEG 2也负责sugiol诱导的STAT 3去磷酸化。使用DU 145小鼠异种移植模型证实了sugiol对细胞生长的抑制作用。我们提出，sugiol抑制STAT 3活性通过一种机制，涉及抑制转酮醇酶，这导致增加的ROS水平和MEG 2激活DU 145细胞。因此，Sugiol是第一个通过调节癌症代谢途径来调节STAT 3活性的化合物，并且我们建议使用Sugiol作为STAT 3途径的抑制剂来治疗具有活化的STAT 3的人实体瘤。(C)2015 Elsevier Inc. All rights reserved.
Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in various human cancers and has been used as a therapeutic target for tumors. This study screened natural products to identify compounds that inhibit STAT3 activity using a STAT3-dependent luciferase reporter system. Sugiol was identified as a compound that decreased luciferase activity in a dose-dependent manner. Sugiol specifically inhibited STAT3 phosphorylation at Tyr-705 in DU145 prostate cells, and this inhibition was independent of the STAT3 upstream kinase. Sugiol induced cell cycle arrest and decreased the expression levels of STAT3 target genes, such as cyclin D1, cyclin A, and survivin. Notably, we observed that sugiol interacted with transketolase, an enzyme in central metabolism, and increased ROS levels leading to the activation of ERR, which inhibits STAT3 activity. The protein phosphatase MEG2 was also responsible for sugiol-induced STAT3 dephosphorylation. The inhibitory effect of sugiol on cell growth was confirmed using the DU145 mouse xenograft model. We propose that sugiol inhibits STAT3 activity through a mechanism that involves the inhibition of transketolase, which leads to increased ROS levels and MEG2 activation in DU145 cells. Therefore, sugiol is the first compound regulating STAT3 activity via modulation of cancer metabolic pathway and we suggest the use of sugiol as an inhibitor of the STAT3 pathway for the treatment of human solid tumors with activated STAT3. (C) 2015 Elsevier Inc. All rights reserved.