Thyroid carcinoma cells are resistant to FAS-mediated apoptosis but sensitive to tumor necrosis factor-related apoptosis-inducing ligand.
Thyroid carcinoma cells are resistant to FAS-mediated apoptosis but sensitive to tumor necrosis factor-related apoptosis-inducing ligand.
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发表时间：
2000-08
期刊：
影响因子：
11.2
通讯作者：
N. Mitsiades;V. Poulaki;S. Tseleni-Balafouta;D. Koutras;I. Stamenkovic
中科院分区：
文献类型：
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作者：
N. Mitsiades;V. Poulaki;S. Tseleni-Balafouta;D. Koutras;I. Stamenkovic
Fas （APO-1/CD95）是肿瘤坏死因子(TNF)/神经生长因子受体超家族的跨膜蛋白，通过其配体（FasL）交联诱导易感的正常细胞和肿瘤细胞凋亡。TNF相关凋亡诱导配体（TRAIL）是最近发现的TNF超家族成员，已被证明通过结合两种细胞表面受体DR4和DR5选择性杀死肿瘤细胞。另外两个TRAIL受体（DcR1和DcR2）不传递凋亡信号，并被认为对TRAIL诱导的细胞凋亡具有保护作用。我们分别用Western blot和免疫组化方法检测了Fas、DR4和DR5在甲状腺癌细胞株和31例甲状腺癌标本中的表达，并检测了甲状腺癌细胞株对Fas和trail诱导的细胞凋亡的敏感性。Fas在大多数甲状腺癌细胞系和组织标本中均有表达。虽然Fas交联不会诱导甲状腺癌细胞凋亡，但Fas介导的凋亡确实在蛋白质合成抑制剂环己亚胺存在的情况下发生，这表明在这些细胞中存在Fas途径的短期抑制剂。Fas交联不能诱导caspase 8的募集和激活，而转染具有组成性活性的caspase 8构建物可以有效地杀死SW579乳头状癌细胞系，这表明假定的抑制剂的作用发生在caspase 8的上游。相比之下，重组TRAIL通过在受体水平激活caspase-10并触发caspase介导的凋亡级联，在12个甲状腺癌细胞系中诱导10个细胞凋亡。对TRAIL的抗性与DcR1或DcR2蛋白表达无关，并且在50%的抗性细胞系中通过蛋白合成抑制来克服。一种髓质癌细胞系对fas和trail诱导的凋亡具有抗性，即使在环己亚胺存在的情况下也是如此，并且对组成型活性caspase-8的转染具有抗性，这表明凋亡途径的不同调控。我们的观察表明，TRAIL通过诱导caspase介导的细胞凋亡，有效地杀死起源于甲状腺滤泡上皮的癌，并可能为甲状腺癌提供潜在的有效治疗试剂。
Fas (APO-1/CD95) is a transmembrane protein of the tumor necrosis factor (TNF)/nerve growth factor receptor superfamily that induces apoptosis in susceptible normal and neoplastic cells upon cross-linking by its ligand (FasL). TNF-related apoptosis-inducing ligand (TRAIL) is a more recently identified member of the TNF superfamily that has been shown to selectively kill neoplastic cells by engaging two cell-surface receptors, DR4 and DR5. Two additional TRAIL receptors (DcR1 and DcR2) do not transmit an apoptotic signal and have been proposed to confer protection from TRAIL-induced apoptosis. We addressed the expression of Fas, DR4, and DR5 in thyroid carcinoma cell lines and in 31 thyroid carcinoma specimens by Western blot analysis and immunohistochemistry, respectively, and tested the sensitivity of thyroid carcinoma cell lines to Fas- and TRAIL-induced apoptosis. Fas was found to be expressed in most thyroid carcinoma cell lines and tissue specimens. Although cross-linking of Fas did not induce apoptosis in thyroid carcinoma cell lines, Fas-mediated apoptosis did occur in the presence of the protein synthesis inhibitor cycloheximide, suggesting the presence of a short-lived inhibitor of the Fas pathway in these cells. Cross-linking of Fas failed to induce recruitment and activation of caspase 8, whereas transfection of a constitutively active caspase 8 construct effectively killed the SW579 papillary carcinoma cell line, arguing that the action of the putative inhibitor occurs upstream of caspase 8. By contrast, recombinant TRAIL induced apoptosis in 10 of 12 thyroid carcinoma cell lines tested, by activating caspase-10 at the receptor level and triggering a caspase-mediated apoptotic cascade. Resistance to TRAIL did not correlate with DcR1 or DcR2 protein expression and was overcome by protein synthesis inhibition in 50% of the resistant cell lines. One medullary carcinoma cell line was resistant to Fas-and TRAIL-induced apoptosis, even in the presence of cycloheximide, and to transfection of constitutively active caspase-8, suggesting a different regulation of the apoptotic pathway. Our observations indicate that TRAIL effectively kills carcinomas that originate from the follicular epithelium of the thyroid gland, by inducing caspase-mediated apoptosis, and may provide a potentially potent therapeutic reagent against thyroid cancer.