Lacour S, Hammann A, Wotawa A, Corcos L, Solary E, Dimanche-Boitrel M T
Institut National de la Santé et de la Recherche Médicale U517, Facultés de Médicine et de Pharmacie, Dijon, France.
Cancer Res. 2001 Feb 15;61(4):1645-51.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a new cytokine that was proposed to specifically induce apoptosis of cancer cells. In tumor cells that are resistant to the cytokine, subtoxic concentrations of chemotherapeutic drugs can restore the response to TRAIL. The present study further explores the mechanisms that determine tumor cell sensitivity to TRAIL by comparing four human colon carcinoma cell lines We show that colon cancer cell sensitivity to TRAIL-induced apoptosis and cytotoxicity correlates with the expression of the death receptors TRAIL-R1 and TRAIL-R2 at the cell surface, as determined by now cytometry, whereas the two decoy receptors TRAIL-R3 and TRAIL-R4 can be detected only in permeabilized cells. Clinically relevant concentrations of cisplatin and doxorubicin sensitize the most resistant colon cancer cell lines to TRAIL-induced cell death without modifying the expression nor the localization of TRAIL receptors in these cells. TRAIL induces the activation of procaspase-8 and triggers caspase-dependent apoptosis off colon cancer cells. Cytotoxic drugs lower the signaling threshold required for TRAIL-induced procaspase-8 activation. In turn, caspase-8 cleaves Bid, a BH3 domain-containing proapoptotic molecule of the Bcl-2 family and activates effector caspases. Together, these data indicate that chemotherapeutic drugs sensitize colon tumor cells to TRAIL-mediated caspase-8 activation and apoptosis.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）是一种新的细胞因子，被认为可特异性诱导癌细胞凋亡。在对该细胞因子耐药的肿瘤细胞中，亚毒性浓度的化疗药物可恢复对TRAIL的反应。本研究通过比较四种人结肠癌细胞系，进一步探讨了决定肿瘤细胞对TRAIL敏感性的机制。我们发现，通过流式细胞术测定，结肠癌细胞对TRAIL诱导的凋亡和细胞毒性的敏感性与细胞表面死亡受体TRAIL-R1和TRAIL-R2的表达相关，而两种诱饵受体TRAIL-R3和TRAIL-R4仅在通透化细胞中可检测到。临床相关浓度的顺铂和阿霉素可使最耐药的结肠癌细胞系对TRAIL诱导的细胞死亡敏感，而不改变这些细胞中TRAIL受体的表达和定位。TRAIL诱导procaspase-8的激活，并触发结肠癌细胞的caspase依赖性凋亡。细胞毒性药物降低了TRAIL诱导procaspase-8激活所需的信号阈值。反过来，caspase-8切割Bid，Bid是Bcl-2家族中一个含BH3结构域的促凋亡分子，并激活效应caspase。总之，这些数据表明化疗药物使结肠肿瘤细胞对TRAIL介导的caspase-8激活和凋亡敏感。
