Arai Midori A, Taguchi Shota, Komatsuzaki Kazuhiro, Uchiyama Kento, Masuda Ayaka, Sampei Mana, Satoh Mamoru, Kado Sayaka, Ishibashi Masami
Graduate School of Pharmaceutical Sciences Chiba University 1-8-1 Inohana, Chuo-ku Chiba 260-8675 Japan.
Division of Clinical Mass Spectrometry Chiba University Hospital 1-8-1 Inohana, Chuo-ku Chiba260-8670 Japan; Chemical Analysis Center Chiba University 1-33 Yayoi-cho, Inage-ku Chiba263-8522 Japan.
ChemistryOpen. 2016 Oct 24;5(6):574-579. doi: 10.1002/open.201600081. eCollection 2016 Dec.
Fuligocandin B () is a novel natural product that can overcome TRAIL resistance. We synthesized enatiomerically pure fuligocandin B () and its derivative 5'-I fuligocandin B (), and found that the latter had an improved biological activity against the human gastric cancer cell line, AGS. We attached a biotin linker and photoactivatable aryl diazirine group to 5'-I fuligocandin B (), and employed a pull-down assay to identify valosin-containing protein (VCP/p97), an AAA ATPase, as a 5'-I fuligocandin B () target protein. Knock-down of VCP by siRNA enhanced sensitivity to TRAIL in AGS cells. In addition, enhanced CHOP and DR5 protein expression, and overall intracellular levels of ubiquitinated protein. These data suggest that endoplasmic reticulum stress caused through VCP inhibition by increases CHOP-mediated DR5 up-regulation, which enhances TRAIL-induced cell death in AGS cells. To the best of our knowledge, this is the first example to show a relationship between VCP and TRAIL-resistance-overcoming activity in cancer cells.
富里戈坎汀B（）是一种新型天然产物，能够克服TRAIL抗性。我们合成了对映体纯的富里戈坎汀B（）及其衍生物5'-I富里戈坎汀B（），并发现后者对人胃癌细胞系AGS具有增强的生物活性。我们将生物素连接体和可光活化的芳基重氮丙啶基团连接到5'-I富里戈坎汀B（）上，并采用下拉实验来鉴定含缬酪肽蛋白（VCP/p97），一种AAA型ATP酶，作为5'-I富里戈坎汀B（）的靶蛋白。通过小干扰RNA敲低VCP可增强AGS细胞对TRAIL的敏感性。此外，还增强了CHOP和DR5蛋白的表达以及泛素化蛋白的整体细胞内水平。这些数据表明，通过抑制VCP所引起的内质网应激增加了CHOP介导的DR5上调，从而增强了TRAIL诱导的AGS细胞死亡。据我们所知，这是首次表明VCP与癌细胞中克服TRAIL抗性活性之间关系的例子。
