Synergistic antitumor effects of radiation and proteasome inhibitor treatment in pancreatic cancer through the induction of autophagy and the downregulation of TRAF6
Synergistic antitumor effects of radiation and proteasome inhibitor treatment in pancreatic cancer through the induction of autophagy and the downregulation of TRAF6
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DOI：
10.1016/j.canlet.2015.05.025
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发表时间：
2015-09-01
期刊：
影响因子：
9.7
通讯作者：
Wang, Ying-Jan
中科院分区：
文献类型：
--
作者：
Chiu, Hui-Wen;Lin, Shu-Wen;Wang, Ying-Jan
90%的人类胰腺癌的特征是激活K-RAS突变。TRAF6是一个癌基因，在k - ras介导的肿瘤发生中起着至关重要的作用。我们研究了电离辐射（IR）和蛋白酶体抑制剂（MG132）联合使用的协同效应。此外，在IR和MG132联合治疗后，我们在体外和原位胰腺癌小鼠模型中分析了TRAF6的表达和人胰腺癌细胞死亡的机制。联合治疗组对人胰腺癌细胞具有协同杀伤作用，并诱导内质网应激。联合治疗组的特点是细胞毒性增强，这是由于抑制TRAF6诱导自噬增加。经3-MA（一种自噬抑制剂）预处理的MIA PaCa-2细胞经MG132和IR处理后，细胞毒性显著降低。下调TRAF6导致细胞凋亡和自噬显著增加。在SCID小鼠原位异种移植模型中，MG 132联合IR治疗可显著增加肿瘤生长延迟时间，降低肿瘤组织中TRAF6的表达。IR联合蛋白酶体抑制剂或TRAF6抑制剂可能代表了一种新的治疗胰腺癌的策略。2015爱思唯尔爱尔兰有限公司版权所有。
Ninety percent of human pancreatic cancer is characterized by activating K-RAS mutations. TRAF6 is an oncogene that plays a vital role in K-RAS-mediated oncogenesis. We investigated the synergistic effect of combining ionizing radiation (IR) and proteasome inhibitor (MG132). Furthermore, following combined treatment with IR and MG132, we analyzed the expression of TRAF6 and the mechanism of human pancreatic cancer cell death in vitro and in an orthotopic pancreatic cancer mouse model. The combined treatment groups displayed synergistic cell killing effects and induced endoplasmic reticulum stress in human pancreatic cancer cells. The combined treatment groups were characterized by enhanced cytotoxicity, which resulted from increased autophagy induction through the inhibition of TRAF6. Significantly reduced cytotoxicity was observed following MG132 and IR treatment of MIA PaCa-2 cells pre-treated with 3-MA (an autophagy inhibitor). Down-regulation of TRAF6 led to a significant increase in apoptosis and autophagy. In an orthotopic xenograft model of SCID mice, combination MG 132 and IR therapy resulted in a significant increase in the tumor growth delay time and a decreased tumor tissue expression of TRAF6. IR combined with a proteasome inhibitor or TRAF6 inhibition could represent a new therapeutic strategy for human pancreatic cancer. (C) 2015 Elsevier Ireland Ltd. All rights reserved.