Laboratory of Chemical Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology 125Gwahakro Yoosunggu, Daejeon 305-806, Republic of Korea.
Laboratory of Chemical Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology 125Gwahakro Yoosunggu, Daejeon 305-806, Republic of Korea; Biomolecular Science, University of Science and Technology in Korea, 125 Gwahakro Yoosunggu, Daejeon 305-806, Republic of Korea.
Biochem Pharmacol. 2015 Sep 1;97(1):38-50. doi: 10.1016/j.bcp.2015.06.033. Epub 2015 Jul 23.
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 ERK, 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.
信号转导子和转录激活子 3（STAT3）在各种人类癌症中持续激活，并已被用作肿瘤的治疗靶点。本研究利用 STAT3 依赖性荧光素酶报告系统筛选天然产物，以鉴定抑制 STAT3 活性的化合物。发现苏醇是一种能以剂量依赖方式降低荧光素酶活性的化合物。苏醇特异性抑制 DU145 前列腺细胞中 STAT3 的酪氨酸 705 磷酸化，这种抑制与 STAT3 上游激酶无关。苏醇诱导细胞周期停滞，并降低 STAT3 靶基因（如 cyclin D1、cyclin A 和 survivin）的表达水平。值得注意的是，我们观察到苏醇与转酮醇酶（一种中心代谢酶）相互作用，并增加 ROS 水平，从而激活 ERK，抑制 STAT3 活性。蛋白磷酸酶 MEG2 也负责苏醇诱导的 STAT3 去磷酸化。使用 DU145 小鼠异种移植模型证实了苏醇对细胞生长的抑制作用。我们提出，苏醇通过抑制转酮醇酶来抑制 STAT3 活性，从而导致 DU145 细胞中 ROS 水平升高和 MEG2 激活。因此，苏醇是第一个通过调节肿瘤代谢途径来调节 STAT3 活性的化合物，我们建议使用苏醇作为治疗激活 STAT3 的人类实体瘤的 STAT3 途径抑制剂。
