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首页> 外文期刊>Oncogene >p53-Mediated upregulation of DcR1 impairs oxaliplatin|[sol]|TRAIL-induced synergistic anti-tumour potential in colon cancer cells
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p53-Mediated upregulation of DcR1 impairs oxaliplatin|[sol]|TRAIL-induced synergistic anti-tumour potential in colon cancer cells

机译：p53介导的DcR1上调损害奥沙利铂| [sol] | TRAIL诱导的结肠癌细胞协同抗肿瘤潜力

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Oxaliplatin has emerged as a major chemotherapeutic drug in the treatment of advanced colorectal cancer, yet like most conventional cancer therapeutics, its efficacy is often compromised due to p53 mutations. Unlike oxaliplatin, tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) triggers apoptosis in a p53-independent manner, and chemotherapy is known to overcome tumour resistance to TRAIL-induced cell death in most cancer cells. Using a panel of colon cancer cell lines, we assessed the ability of oxaliplatin to sensitize to TRAIL-induced apoptosis. We demonstrate that while both drugs additively or synergistically induced apoptosis in almost all cell lines tested, p53 wild-type colon cancer cells such as HCT116, LS513 or LS174T remained resistant. Impaired TRAIL-induced cell death resulted from a strong p53 dependent, oxaliplatin-mediated, DcR1 receptor expression increase. According to our finding, downregulation of DcR1 using siRNA, in p53 wild-type colon cancer cells, restored oxaliplatin/TRAIL synergistic apoptotic activity. On the contrary, exogenous DcR1 overexpression in SW480, a p53-mutated cell line, abolished the synergy between the two drugs. Altogether we demonstrate for the first time that p53 negatively regulates oxaliplatin-mediated TRAIL-induced apoptotic activity through DcR1 upregulation. Our findings could have important implications for future therapeutic strategies, and suggest that the association oxaliplatin/TRAIL should be restricted to patients harbouring a non-functional p53 protein.
机译：奥沙利铂已经成为治疗晚期结直肠癌的主要化学治疗药物，但与大多数常规癌症治疗剂一样，其功效通常由于p53突变而受损。与奥沙利铂不同，肿瘤坏死因子相关的凋亡诱导配体（TRAIL）以p53独立的方式触发凋亡，并且已知化学疗法能克服大多数癌细胞对TRAIL诱导的细胞死亡的抗性。使用一组结肠癌细胞系，我们评估了奥沙利铂对TRAIL诱导的细胞凋亡敏感的能力。我们证明，虽然两种药物在几乎所有测试的细胞系中都可累加或协同诱导凋亡，但p53野生型结肠癌细胞如HCT116，LS513或LS174T仍具有抗性。 TRAIL诱导的细胞死亡受损是由于强烈依赖p53的，奥沙利铂介导的DcR1受体表达增加所致。根据我们的发现，在p53野生型结肠癌细胞中使用siRNA下调DcR1，恢复了奥沙利铂/ TRAIL协同凋亡活性。相反，p480突变的细胞系SW480中的外源性DcR1过表达消除了这两种药物之间的协同作用。总之，我们首次证明了p53通过DcR1上调负调控奥沙利铂介导的TRAIL诱导的细胞凋亡活性。我们的发现可能对未来的治疗策略具有重要意义，并表明奥沙利铂/ TRAIL的联合应仅限于携带非功能性p53蛋白的患者。

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