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Homoharringtonine could induce quick protein synthesis of PSMD11 through activating MEK1/ERK1/2 signaling pathway in pancreatic cancer cells
Author(s) -
Wang Lele,
Zhao Linlin,
Wei Guo,
Saur Dieter,
Seidler Barbara,
Wang Junyan,
Wang Chuanxin,
Qi Tonggang
Publication year - 2018
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.26847
Subject(s) - homoharringtonine , pancreatic cancer , apoptosis , cancer research , signal transduction , cancer , pancreas , medicine , microbiology and biotechnology , chemistry , biology , biochemistry , myeloid leukemia
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.