Central Research Laboratory, The Second Hospital of Shandong University, Jinan, China.
Department of Dermatology, The Second Hospital of Shandong University, Jinan, China.
J Cell Biochem. 2018 Aug;119(8):6644-6656. doi: 10.1002/jcb.26847. Epub 2018 Apr 17.
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most devastating disease with the 5-year survival rate less than 6%. In this study, we investigated if inhibiting protein synthesis directly with homoharringtonine (HHT) could induce acute apoptosis in pancreatic cancer cells through quick depletion of multiple short-lived critical members of the central proteome, example, PSMD11(26S proteasome non-ATPase regulatory subunit 11). It was shown that although HHT could inhibit proliferation and growth of MiaPaCa-2 and PANC-1 cells in a time- and dose-dependent manner, only part of pancreatic cancer cells could be induced to die through acute apoptosis. Mechanistic studies showed that HHT could induce quick protein synthesis of PSMD11 through activating MEK1/ERK1/2 signaling pathway in pancreatic cancer cells. Inhibiting MEK1/ERK1/2 pathway with sorafenib could improve the cytotoxity of HHT in vitro and in a genetically engineered mouse model of pancreatic cancer. These results suggest that quick induction of PSMD11 or other acute apoptosis inhibitors through activation of the MEK1/ERK1/2 signaling pathway may be one of the important surviving mechanism which can help pancreatic cancer cells avoid acute apoptosis, it may have significant implications for the targeted therapy of pancreatic ductal adenocarcinoma.
胰腺导管腺癌（PDAC）仍然是最具破坏性的疾病之一，5 年生存率低于 6%。在这项研究中，我们研究了是否可以通过快速耗尽中央蛋白质组的多个短寿命关键成员（例如 PSMD11（26S 蛋白酶体非 ATP 酶调节亚基 11）），直接使用高三尖杉酯碱（HHT）抑制蛋白质合成来诱导胰腺癌细胞发生急性细胞凋亡。结果表明，尽管 HHT 可以时间和剂量依赖性方式抑制 MiaPaCa-2 和 PANC-1 细胞的增殖和生长，但只有部分胰腺癌细胞可以通过急性细胞凋亡诱导死亡。机制研究表明，HHT 可以通过激活 MEK1/ERK1/2 信号通路在胰腺癌细胞中快速诱导 PSMD11 的蛋白质合成。用索拉非尼抑制 MEK1/ERK1/2 通路可以提高 HHT 在体外和胰腺导管腺癌基因工程小鼠模型中的细胞毒性。这些结果表明，通过激活 MEK1/ERK1/2 信号通路快速诱导 PSMD11 或其他急性细胞凋亡抑制剂可能是帮助胰腺癌细胞避免急性细胞凋亡的重要存活机制之一，这可能对胰腺导管腺癌的靶向治疗具有重要意义。
