School of Bioconvergence, Kyungnam University, Changwon 51767, Republic of Korea.
J Microbiol Biotechnol. 2020 May 28;30(5):733-738. doi: 10.4014/jmb.2002.02002.
Glucose deprivation and hypoxia frequently occur in solid tumor cells, including pancreatic cancer cells. Glucose deprivation activates the unfolded protein response (UPR) and causes the upregulation of glucose-regulated protein 78 (GRP78). Induction of GRP78 has been shown to protect cancer cells. Therefore, shutting down of GRP78 expression may be a novel strategy in anticancer drug development. Based on this understanding, a screening system established for anticancer agents that exhibit selective cytotoxicity on pancreatic cancer cells under glucose-deprived conditions. To test this hypothesis, the new compounds isolated, pancastatin A (PST-A) and B (PSTB), from Ponciri Fructus. PST-A and B were identified as glabretal triterpenoid moieties by electrospray ionization mass spectrometry and nuclear magnetic resonance spectroscopic methods. PST-A and B suppressed the accumulation of the UPR hallmark gene, GRP78, during glucose deprivation. Furthermore, PST-A and B showed selective cytotoxicity on PANC-1 pancreatic cancer cells under glucose deprivation. Interestingly, PST-A and B had no effect on these cells under normal growth conditions. Our results suggest that PST-A and B act as novel therapeutic agents to induce selective cell death in glucose-deprived pancreatic cancer cells.
葡萄糖剥夺和缺氧经常发生在实体肿瘤细胞中，包括胰腺癌细胞。葡萄糖剥夺会激活未折叠蛋白反应 (UPR)，并导致葡萄糖调节蛋白 78 (GRP78) 的上调。已证明诱导 GRP78 的表达可以保护癌细胞。因此，关闭 GRP78 的表达可能是抗癌药物开发的一种新策略。基于这一理解，建立了一种筛选系统，用于筛选在葡萄糖剥夺条件下对胰腺癌细胞具有选择性细胞毒性的抗癌药物。为了验证这一假说，从枳椇果实中分离得到的新化合物，蓬砂 A (PST-A) 和蓬砂 B (PSTB)。通过电喷雾电离质谱和核磁共振波谱方法鉴定 PST-A 和 B 为 glabretal 三萜类部分。PST-A 和 B 在葡萄糖剥夺时抑制 UPR 特征基因 GRP78 的积累。此外，PST-A 和 B 在葡萄糖剥夺下对 PANC-1 胰腺癌细胞表现出选择性细胞毒性。有趣的是，PST-A 和 B 在正常生长条件下对这些细胞没有影响。我们的结果表明，PST-A 和 B 可作为诱导葡萄糖剥夺的胰腺癌细胞选择性细胞死亡的新型治疗剂。
