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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Requirement of p53 targets in chemosensitization of colonic carcinoma to death ligand therapy
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Requirement of p53 targets in chemosensitization of colonic carcinoma to death ligand therapy

机译：p53靶标在结肠癌对死亡配体疗法的化学增敏中的需求

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摘要

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) exhibits specific tumoricidal activity and is under development for cancer therapy. Mismatch-repair-deficient colonic tumors evade TRAIL-induced apoptosis through mutational inactivation of Bax, but chemotherapeutics including Camptosar (CPT-11) restore TRAIL sensitivity. However, the signaling pathways in restoring TRAIL sensitivity remain to be elucidated. Here, we imaged p53 transcrip- tional activity in Bax~(-/-) carcinomas by using bioluminescence, in vivo, and find that p53 is required for sensitization to TRAIL by CPT-11. Small interfering RNAs directed at proapoptotic p53 targets reveal TRAIL receptor KILLER/DR5 contributes significantly to TRAIL sensitization, whereas Bak plays a minor role. Caspase 8 inhibition protects both CPT-11 pretreated wild-type and Bax~(-/-) HCT116 cells from TRAIL-induced apoptosis, whereas caspase 9 inhibition only rescued the wild-type HCT116 cells from death induced by TRAIL. The results suggest a conversion in the apoptotic mechanism in HCT116 colon carcinoma from a type Ⅱ pathway involving Bax and the mitochondria to a type Ⅰ pathway involving efficient extrinsic pathway caspase activation. In contrast to Bax~(-/-) cells, Bak-deficient human cancers undergo apoptosis in response to TRAIL or CPT-11, implying that these proteins have nonoverlapping functions. Our studies elucidate a mechanism for restoration of TRAIL sensitivity in MMR-deficient Bax~(-/-) human cancers through p53-dependent activation of KILLER/DR5 and reconstitution of a type Ⅰ death pathway. Efforts to identify agents that up-regulate DR5 may be useful in cancer therapies restoring TRAIL sensitivity.
机译：肿瘤坏死因子相关的凋亡诱导配体（TRAIL）具有特定的杀肿瘤活性，并且正在开发用于癌症治疗的方法。失配修复缺陷的结肠肿瘤通过Bax的突变失活来逃避TRAIL诱导的细胞凋亡，但包括Camptosar（CPT-11）在内的化学治疗剂可恢复TRAIL敏感性。然而，恢复TRAIL敏感性的信号传导途径仍有待阐明。在这里，我们通过体内生物发光技术对Bax〜（-/-）癌中的p53转录活性进行了成像，发现p53是CPT-11对TRAIL致敏所必需的。针对促凋亡p53靶标的小分子干扰RNA显示，TRAIL受体KILLER / DR5对TRAIL致敏作用显着，而Bak则起次要作用。 Caspase 8抑制作用可保护CPT-11预处理的野生型和Bax〜（-/-）HCT116细胞免受TRAIL诱导的凋亡，而caspase 9抑制作用仅使野生型HCT116细胞免于TRAIL诱导的死亡。结果提示HCT116结肠癌的凋亡机制从涉及Bax和线粒体的Ⅱ型途径向涉及有效外源胱天蛋白酶激活的Ⅰ型途径转变。与Bax-（-/-）细胞相反，缺乏Bak的人类癌症发生细胞凋亡以响应TRAIL或CPT-11，这意味着这些蛋白质具有非重叠功能。我们的研究阐明了通过p53依赖性激活KILLER / DR5并重建Ⅰ型死亡途径来恢复MMR缺陷型Bax〜（-/-）人类癌症TRAIL敏感性的机制。鉴定上调DR5的药物可能有助于恢复TRAIL敏感性的癌症治疗。

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