Alteration of the Intrinsic Apoptosis Pathway Is Involved in Notch-induced Chemoresistance to Gemcitabine in Pancreatic Cancer
Alteration of the Intrinsic Apoptosis Pathway Is Involved in Notch-induced Chemoresistance to Gemcitabine in Pancreatic Cancer
复制标题
内在凋亡途径的改变与Notch诱导的胰腺癌吉西他滨化疗耐药有关
DOI：
10.1016/j.arcmed.2013.10.001
复制
发表时间：
2014-01-01
影响因子：
7.7
通讯作者：
Shu, Hong
中科院分区：
文献类型：
--
作者：
Du, Xiao;Zhao, Yu-pei;Shu, Hong
背景和目标。化疗耐药性是胰腺癌（PC）治疗的主要挑战。有限的数据表明，Notch信号通路的成员参与PC对吉西他滨（GEM）的耐药性。然而，还需要进一步的证据，潜在的机制仍有待阐明。本研究旨在探讨内源性凋亡途径的改变在Notch诱导的PC GEM耐药中的作用。Notch信号通路在三种PC细胞系（AsPC-1、BxPC-3和MIA PaCa-2）中分别通过γ-分泌酶抑制和Notch胞内结构域（NICD）过表达而被抑制或激活。随后的分析包括GEM对细胞增殖的抑制率、细胞凋亡和参与内源性凋亡途径的蛋白质表达。GEM处理后Hes-1表达显著升高，表明Notch激活。通过DAPT（一种γ-分泌酶抑制剂）抑制Notch信号通路，导致GEM在所有PC细胞系中的抑制率显著增加。另外，凋亡细胞增多，caspase-3活性升高，Bax表达上调，Bcl-2和Bcl-xL表达下调。相反，瞬时转染NICD，这增强了Notch信号的活性，导致对GEM的化疗敏感性显着降低。Notch诱导的PC细胞对GEM耐药与内源性凋亡途径的改变有关。(C)2014年墨西哥社会保障局。由爱思唯尔公司出版
Background and Aims. Chemoresistance is a major challenge in pancreatic cancer (PC) treatment. Limited data have shown that members of the Notch signaling pathway are involved in resistance to gemcitabine (GEM) in PC. However, further evidence is needed and the underlying mechanisms remain to be elucidated. The current study aims to investigate the role of alterations of the intrinsic apoptosis pathway in Notch-induced GEM resistance of PC.Methods. The Notch signaling pathway was inhibited or activated in three PC cell lines (AsPC-1, BxPC-3, and MIA PaCa-2) by gamma-secretase inhibition and Notch intracellular domain (NICD) overexpression, respectively. Subsequent analyses included inhibition rates of cell proliferation by GEM, cell apoptosis, and expression of proteins involved in the intrinsic apoptosis pathway.Results. Hes-1 expression was significantly elevated after GEM treatment, indicating Notch activation. Inhibition of the Notch signaling pathway by DAPT, a gamma-secretase inhibitor, resulted in a significant increase of the inhibition rates by GEM in all PC cell lines. In addition, there was more frequent apoptosis, higher caspase-3 activity, up-regulation of Bax, and down-regulation of Bcl-2 and Bcl-xL. Conversely, transient transfection of NICD, which enhances the activity of the Notch signaling, caused a remarkable decrease of the chemosensitivity to GEM.Conclusions. An alteration of the intrinsic apoptosis pathway is involved in Notch-induced chemoresistance to GEM in PC cells. (C) 2014 IMSS. Published by Elsevier Inc.