TRAIL receptor signaling regulation of chemosensitivity in vivo but not in vitro.
TRAIL receptor signaling regulation of chemosensitivity in vivo but not in vitro.
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DOI：
10.1371/journal.pone.0014527
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发表时间：
2011-01-14
期刊：
影响因子：
3.7
通讯作者：
Thorburn A
中科院分区：
文献类型：
--
作者：
Menke C;Goncharov T;Qamar L;Korch C;Ford HL;Behbakht K;Thorburn A
肿瘤坏死因子相关凋亡诱导配体（TRAIL）和Fas配体（FasL）的信号传导已被提出有助于用各种其他抗癌剂处理的肿瘤细胞的化学敏感性。然而，这些影响的重要性以及体外和体内是否存在差异尚不清楚。为了评估死亡受体途径对这种敏感性的相对贡献，并确定这些效应是否是肿瘤细胞固有的，我们比较了同基因BJAB人淋巴瘤细胞的化学敏感性，其中Fas和TRAIL受体或仅TRAIL受体使用衔接蛋白FADD的突变体或通过改变同源框转录因子Six 1的表达被抑制。TRAIL受体的抑制不影响各种抗癌剂的体外肿瘤细胞杀伤，表明化学敏感性不受肿瘤细胞固有的死亡受体信号传导激活的显著影响。然而，当在NOD/SCID小鼠模型中测试时，选择性抑制TRAIL受体信号传导导致体内肿瘤消退和清除减少。这些数据表明，肿瘤细胞中的TRAIL受体信号传导可以决定体内而不是体外的化学敏感性，因此意味着TRAIL抗性使肿瘤对常规细胞毒性抗癌药物以及直接靶向TRAIL受体的药物不太敏感。
Signaling by Tumor Necrosis Factor-Related Apoptosis Inducing Ligand (TRAIL) and Fas ligand (FasL) has been proposed to contribute to the chemosensitivity of tumor cells treated with various other anti-cancer agents. However, the importance of these effects and whether there are differences in vitro and in vivo is unclear. To assess the relative contribution of death receptor pathways to this sensitivity and to determine whether these effects are intrinsic to the tumor cells, we compared the chemosensitivity of isogenic BJAB human lymphoma cells where Fas and TRAIL receptors or just TRAIL receptors were inhibited using mutants of the adaptor protein FADD or by altering the expression of the homeobox transcription factor Six1. Inhibition of TRAIL receptors did not affect in vitro tumor cell killing by various anti-cancer agents indicating that chemosensitivity is not significantly affected by the tumor cell-intrinsic activation of death receptor signaling. However, selective inhibition of TRAIL receptor signaling caused reduced tumor regression and clearance in vivo when tested in a NOD/SCID mouse model. These data show that TRAIL receptor signaling in tumor cells can determine chemosensitivity in vivo but not in vitro and thus imply that TRAIL resistance makes tumors less susceptible to conventional cytotoxic anti-cancer drugs as well as drugs that directly target the TRAIL receptors.
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