期刊
INTERNATIONAL JOURNAL OF MEDICAL SCIENCES
卷 16, 期 11, 页码 1412-1423出版社
IVYSPRING INT PUBL
DOI: 10.7150/ijms.34398
关键词
Gastric cancer; TRAIL; Bortezomib; DR4; DR5; ERK; p21(cip1/waf1)
资金
- Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Education [2015R1D1A1A01058830]
- National Research Foundation of Korea [2015R1D1A1A01058830] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Resistance against tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cell death of cancer cells is a major obstacle in clinical application of TRAIL. Variable response to TRAIL of gastric cancer cells, synergy of TRAIL with bortezomib and potential mechanisms behind the phenomena were investigated in this study. The response to TRAIL varied among six gastric cancer cell lines, which correlated with the expression of apoptotic TRAIL receptors. Analysis of TCGA gene expression data showed that DR4 expression correlated with DR5 in gastric cancer. Although higher expression of DR4 was significantly associated with lower T, N and TNM stages, neither DR4 nor DR5 expression meaningfully influenced overall survival rate. Combined treatment of TRAIL with bortezomib resulted in strong synergistic response with enhanced activation of caspases-8, -9 and -3, and increased Annexin V-binding cell fractions in TRAIL-resistant SNU-216 cells. Bortezomib increased the expression of p21(cip1/waf1), but p21(cip1/waf1) silencing did not restore cell viability significantly. Bortezomib also increased DR5 expression and knockdown of DR5 expression significantly recovered cell viability reduced by the combination treatment. Bortezomib decreased phosphorylation of ERK1/2, but increased that of JNK. Treatment with either an ERK1/2 inhibitor U0126 or a JNK inhibitor SP600125 rescued SNU-216 from dying of bortezomib or combined treatment. However, upregulation of DR5 by bortezomib was knocked down only by inhibition of ERK1/2 activation significantly, but not by JNK activity inhibition. In summary, upregulation of DR5 by bortezomib is of critical significance in the synergy of bortezomib with TRAIL in apoptosis of TRAIL-resistant SNU-216 and that activity of ERK1/2 is required in the bortezomib-induced DR5 overexpression.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据