Laboratory of Chemical Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahakro, Daejeon, 34141, Republic of Korea.
Laboratory of Chemical Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahakro, Daejeon, 34141, Republic of Korea; Department of Biology, Chungnam National University, Daejeon, 34134, Republic of Korea.
Cancer Lett. 2018 Oct 10;434:42-55. doi: 10.1016/j.canlet.2018.07.015. Epub 2018 Jul 18.
It is reported that 2'-hydroxycinnamaldehyde (HCA), isolated from cinnamon, has anti-tumor effects through the modulation of multi-target molecules. In this study, we identified pyruvate kinase M2 (PKM2) as a direct target of HCA by use of biochemical methods including affinity chromatography, drug affinity responsive target stability, and cellular thermal shift assay. PKM2 is up-regulated in multiple cancer types and is considered as a potential target for cancer therapy. HCA binds directly to PKM2 and selectively decreases the phosphorylation of PKM2 at Tyr105, indicating a potential anti-proliferative effect on prostate cancer cells. As a PKM2 activator, HCA increases pyruvate kinase activity by promoting the tetrameric state of PKM2. However, HCA suppresses protein kinase activity of PKM2 by decreasing the phosphorylation at Tyr105. Moreover, this leads to a decrease of PKM2-mediated STAT3 phosphorylation at Tyr705 and a down-regulation of target genes, including MEK5 and cyclin D1. Furthermore, HCA suppresses tumor growth and the release of tumor extracellular vesicles in vivo by inhibiting the phosphorylation of PKM2. Collectively, our results suggest that HCA may be a potential anticancer agent targeting PKM2 in cancer progression.
据报道，肉桂中分离得到的 2'-羟基肉桂醛（HCA）通过调节多种靶分子发挥抗肿瘤作用。在这项研究中，我们通过生化方法包括亲和层析、药物亲和反应靶标稳定性和细胞热转移测定，确定丙酮酸激酶 M2（PKM2）是 HCA 的直接靶标。PKM2 在多种癌症类型中上调，被认为是癌症治疗的潜在靶点。HCA 直接与 PKM2 结合，并选择性地下调 PKM2 在 Tyr105 上的磷酸化，表明对前列腺癌细胞具有潜在的抗增殖作用。作为 PKM2 激活剂，HCA 通过促进 PKM2 的四聚体状态增加丙酮酸激酶活性。然而，HCA 通过降低 Tyr105 上的磷酸化来抑制 PKM2 的蛋白激酶活性。此外，这导致 PKM2 介导的 STAT3 在 Tyr705 上的磷酸化减少和靶基因（包括 MEK5 和细胞周期蛋白 D1）下调。此外，HCA 通过抑制 PKM2 的磷酸化在体内抑制肿瘤生长和肿瘤细胞外囊泡的释放。总之，我们的研究结果表明，HCA 可能是一种针对癌症进展中 PKM2 的潜在抗癌药物。
