Laboratory of Chemical Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahakro, Daejeon 34141, Korea.
KRIBB School of Bioscience, University of Science and Technology in Korea, Daejeon 34113, Korea.
Molecules. 2021 Oct 14;26(20):6204. doi: 10.3390/molecules26206204.
Signal transducer and activator of transcription 3 (STAT3) plays a critical role in the formation and growth of human cancer. Therefore, STAT3 is a therapeutic target for cancer drug discovery. Acacetin, a flavone present in various plants, inhibits constitutive and inducible STAT3 activation in STAT3-activated DU145 prostate cancer cells. Acacetin inhibits STAT3 activity by directly binding to STAT3, which we confirmed by a pull-down assay with a biotinylated compound and two level-free methods, namely, a drug affinity responsive target stability (DARTS) experiment and a cellular thermal shift assay (CETSA). Acacetin inhibits STAT3 phosphorylation at the tyrosine 705 residue and nuclear translocation in DU145 cells, which leads to the downregulation of STAT3 target genes. Acacetin then induces apoptosis in a time-dependent manner. Interestingly, acacetin induces the production of reactive oxygen species (ROS) that are not involved in the acacetin-induced inhibition of STAT3 activation because the suppressed p-STAT3 level is not rescued by treatment with GSH or NAC, which are general ROS inhibitors. We also found that acacetin inhibits tumor growth in xenografted nude mice. These results suggest that acacetin, as a STAT3 inhibitor, could be a possible drug candidate for targeting STAT3 for the treatment of cancer in humans.
信号转导子和转录激活子 3（STAT3）在人类癌症的形成和生长中起着关键作用。因此，STAT3 是癌症药物发现的治疗靶点。白杨素是存在于多种植物中的一种类黄酮，可抑制 STAT3 激活的 DU145 前列腺癌细胞中组成型和诱导型 STAT3 的激活。白杨素通过直接与 STAT3 结合来抑制 STAT3 活性，我们通过生物素化化合物的下拉测定和两种无标记方法（药物亲和反应靶标稳定性（DARTS）实验和细胞热转移测定（CETSA））证实了这一点。白杨素抑制 DU145 细胞中 STAT3 酪氨酸 705 残基的磷酸化和核转位，从而下调 STAT3 靶基因。白杨素随后以时间依赖性方式诱导细胞凋亡。有趣的是，白杨素诱导活性氧（ROS）的产生，而 ROS 的产生不参与白杨素诱导的 STAT3 激活抑制，因为用 GSH 或 NAC 处理不能挽救被抑制的 p-STAT3 水平，GSH 和 NAC 是通用的 ROS 抑制剂。我们还发现白杨素抑制异种移植裸鼠中的肿瘤生长。这些结果表明，作为 STAT3 抑制剂的白杨素可能是针对 STAT3 治疗人类癌症的候选药物。
