Bcl-xL inhibition by molecular-targeting drugs sensitizes human pancreatic cancer cells to TRAIL.
Bcl-xL inhibition by molecular-targeting drugs sensitizes human pancreatic cancer cells to TRAIL.
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DOI：
10.18632/oncotarget.5881
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发表时间：
2015-12-08
期刊：
影响因子：
--
通讯作者：
Harada M
中科院分区：
文献类型：
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作者：
Hari Y;Harashima N;Tajima Y;Harada M
肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）在各种类型的癌细胞中诱导凋亡而不损伤正常细胞。然而，就胰腺癌而言，并非所有癌细胞都对TRAIL敏感。在这项研究中，我们检查了一组人胰腺癌细胞系的TRAIL敏感性，并研究了Bcl-2家族抑制剂对其对TRAIL反应的影响。ABT-263和ABT-737均抑制Bcl-2、Bcl-xL和Bcl-w的功能。在所测试的9种胰腺癌细胞系中，6种显示出对TRAIL无敏感性或低敏感性，这与Bcl-xL的蛋白表达相关。ABT-263显著地使四种细胞系（AsPC-1、Panc-1、CFPAC-1和Panc10.05）对TRAIL敏感，具有降低的细胞活力和增加的凋亡。通过siRNA转染，Bcl-xL而不是Bcl-2的敲低增加了AsPC-1和Panc-1细胞对TRAIL的敏感性。ABT-263处理对Bcl-2、Bcl-xL或c-FLIPs的蛋白表达没有影响。在Panc-1细胞中，ABT-263增加了死亡受体（DR）5的表面表达; NF-κB通路参与了这种增加，而不是内质网应激。在异种移植小鼠模型中，TRAIL和ATB-737的组合抑制了AsPC-1和Panc-1细胞的体内肿瘤生长。这些结果表明，Bcl-xL是负责人胰腺癌细胞中的TRAIL抗性，Bcl-2家族抑制剂可以代表有前途的试剂，以敏化人胰腺癌DR靶向治疗。
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces apoptosis in various types of cancer cells without damaging normal cells. However, in terms of pancreatic cancer, not all cancer cells are sensitive to TRAIL. In this study, we examined a panel of human pancreatic cancer cell lines for TRAIL sensitivity and investigated the effects of Bcl-2 family inhibitors on their response to TRAIL. Both ABT-263 and ABT-737 inhibited the function of Bcl-2, Bcl-xL, and Bcl-w. Of the nine pancreatic cancer cell lines tested, six showed no or low sensitivity to TRAIL, which correlated with protein expression of Bcl-xL. ABT-263 significantly sensitized four cell lines (AsPC-1, Panc-1, CFPAC-1, and Panc10.05) to TRAIL, with reduced cell viability and increased apoptosis. Knockdown of Bcl-xL, but not Bcl-2, by siRNA transfection increased the sensitivity of AsPC-1 and Panc-1 cells to TRAIL. ABT-263 treatment had no effect on protein expression of Bcl-2, Bcl-xL, or c-FLIPs. In Panc-1 cells, ABT-263 increased the surface expression of death receptor (DR) 5; the NF-κB pathway, but not endoplasmic reticulum stress, participated in the increase. In xenograft mouse models, the combination of TRAIL and ATB-737 suppressed the in vivo tumor growth of AsPC-1 and Panc-1 cells. These results indicate that Bcl-xL is responsible for TRAIL resistance in human pancreatic cancer cells, and that Bcl-2 family inhibitors could represent promising reagents to sensitize human pancreatic cancers in DR-targeting therapy.