Scatter factor protects tumor cells against apoptosis caused by TRAIL.
Scatter factor protects tumor cells against apoptosis caused by TRAIL.
复制标题
分散因子可保护肿瘤细胞免受 TRAIL 引起的细胞凋亡。
DOI：
10.1097/cad.0b013e32832afc3b
复制
发表时间：
2010
影响因子：
2.3
通讯作者：
Rosen,EliotM
中科院分区：
文献类型：
--
作者：
Fan,Saijun;Meng,Qinghui;Laterra,JohnJ;Rosen,EliotM
散点因子（SF）及其受体c-Met在多种肿瘤类型中均过表达，其表达常与不良预后相关。肿瘤坏死因子相关凋亡诱导配体（tumor necrosis factor-related apoptosis-inducing ligand， TRAIL）是一种被提出的肿瘤特异性化疗药物，但其临床应用受到肿瘤获得TRAIL耐药性的限制。本研究的目的是确定SF是否以及如何保护肿瘤细胞对抗TRAIL，以及SF诱导的TRAIL耐药是否可以逆转。我们采用MTT法、台盼蓝染色排除法、细胞凋亡法、RNA干扰法、荧光素酶报告基因法、免疫沉淀/western blotting等细胞生物学技术，研究SF对培养的人肿瘤细胞对TRAIL的保护作用。SF在多种人前列腺癌和乳腺癌细胞系中赋予TRAIL抗性。SF抑制trail诱导的caspase-3激活、聚（adp -核糖）聚合酶裂解和细胞死亡。SF对TRAIL的保护需要c-Akt；但与对阿霉素的保护不同，它不需要Src信号或核因子- κ b激活的经典途径。对TRAIL的保护作用可通过敲低X-linked inhibitor of apoptosis或FLICE-inhibitor protein (FLIP)（死亡诱导信号复合物的一个组成部分）而被阻断。我们发现c-Met与几种TRAIL受体物理结合，SF调节其蛋白稳定性。一种新的c-Met小分子抑制剂（PHA665752）和一种环氧化酶2抑制剂阻断了对TRAIL的保护作用。总之，这些发现阐明了SF/c-Met过表达肿瘤中TRAIL耐药的潜在机制，并确定了逆转这种耐药的可能方法。
Scatter factor (SF) and its receptor c-Met are overexpressed in various tumor types, and their expression often correlates with a poor prognosis. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), is a proposed tumor-specific chemotherapy agent, but its clinical usage is limited by acquisition of TRAIL resistance by tumors. The goals of this study were to determine whether and how SF protects tumor cells against TRAIL and whether SF-induced TRAIL resistance could be reversed. We used MTT assays, trypan blue dye exclusion assays, apoptosis assays, RNA interference, luciferase reporter assays, immunoprecipitation/western blotting, and other cell biological techniques to study SF protection of cultured human tumor cells against TRAIL. SF conferred resistance to TRAIL in various human prostate carcinoma and breast carcinoma cell lines. SF inhibited TRAIL-induced caspase-3 activation, poly (ADP-ribose) polymerase cleavage, and cell death. SF protection against TRAIL required c-Akt; but unlike protection against adriamycin, it did not require Src signaling or the classical pathway of nuclear factor-kappaB activation. Protection against TRAIL was blocked by knockdown of X-linked inhibitor of apoptosis or FLICE-inhibitor protein (FLIP)(a component of the death-inducing signaling complex). We found that c-Met physically associates with several TRAIL receptors and SF regulates their protein stability. Protection against TRAIL was blocked by a novel small molecule inhibitor of c-Met (PHA665752) and by an inhibitor of cyclooxygenase 2. In conclusion, these findings elucidate potential mechanisms of TRAIL resistance in tumors that overexpress the SF/c-Met and identify possible means of reversing this resistance.