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首页> 外文期刊>Cell cycle >Interleukin-6 affects cell death escaping mechanisms acting on Bax-Ku70-Clusterin interactions in human colon cancer progression.
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Interleukin-6 affects cell death escaping mechanisms acting on Bax-Ku70-Clusterin interactions in human colon cancer progression.

机译：白细胞介素6影响在人类结肠癌进展中作用于Bax-Ku70-簇蛋白相互作用的逃避细胞死亡的机制。

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摘要

Activation of pro-survival pathways and apoptotic cell death escape are considered hallmarks of oncogenic cell transformation. Tissue microenvironment strongly influences tumorigenesis, redirecting some pathways versus a persisting pro-survival state. Here, we report evidence on the role of interleukin 6 (IL-6) in affecting pro-survival pathways in colon cancer progression, modulating the expression and the molecular interactions among the pro-apoptotic factor Bax, the DNA repair proteins Ku70/86 and Clusterin isoforms. In human colorectal carcinomas (n = 50) at different stages of disease, we found an increased IL-6 production, the loss of Ku86 and Clusterin 50-55 kDa pro-apoptotic isoform. Conversely, we observed the overexpression of Bax and the 40 kDa prosurvival sClusterin (sCLU) isoform. Bax co-localized with Ku70 that was found atypically expressed in the cytoplasm of advanced stage colon cancers (Dukes'C-D; n = 22). IL-6 treatment of a colon cancer cell line, Caco-2, modulated the expression ofgenes involved in tumor invasion and apoptosis, as observed by microarrays. In particular, IL-6 downmodulated Bax expression at mRNA level. Concomitantly, IL-6 exposure influenced Bax also at protein level acting on the Bax-Ku70-sCLU physical interactions in the cytoplasm, by affecting the Ku70 acetylation and phosphorylation state, thus leading to the inhibition of Bax pro-apoptotic activity. In addition, we found that IL-6 treatment induced a significant downregulation of Ku86 and a strong increase of sCLU, confirming tumor biopsies data. In contrast Somatostatin treatment of Caco-2 cells was able to restore apoptosis, demonstrating that Ku70-Bax-CLU interactions could be dynamically modulated. Hence, IL-6 could favor tumor expansion, promoting cell survival and apoptosis escape throughout the different stages of tumor evolution. Uncovering the molecular mechanisms of action of these factors may offer strategies for selectively manipulate the cancer cells sensitivity to therapy.
机译：促存活途径的激活和凋亡细胞死亡逃逸被认为是致癌细胞转化的标志。组织微环境强烈影响肿瘤的发生，与持久的生存状态相比，改变了某些途径。在这里，我们报告了关于白介素6（IL-6）在影响结肠癌进展中的生存途径，调节凋亡因子Bax，DNA修复蛋白Ku70 / 86和DNA之间的表达和分子相互作用的作用的证据。簇蛋白同工型。在人类不同阶段的大肠癌（n = 50）中，我们发现IL-6产量增加，Ku86和Clusterin的凋亡前体亚型50-55 kDa减少。相反，我们观察到过表达Bax和40 kDa存活的sClusterin（sCLU）亚型。 Bax与Ku70共定位，后者在晚期结肠癌的细胞质中非典型表达（Dukes'C-D; n = 22）。微阵列观察到，IL-6对结肠癌细胞系Caco-2的治疗可调节参与肿瘤侵袭和凋亡的基因的表达。特别地，IL-6在mRNA水平下调了Bax表达。同时，IL-6暴露也通过影响Ku70的乙酰化和磷酸化状态，在蛋白水平上影响Bax，从而影响Bax-Ku70-sCLU在细胞质中的物理相互作用，从而导致Bax促凋亡活性的抑制。此外，我们发现IL-6治疗诱导Ku86的显着下调和sCLU的强烈增加，从而证实了肿瘤活检数据。相反，生长抑素对Caco-2细胞的治疗能够恢复细胞凋亡，表明Ku70-Bax-CLU相互作用可以动态调节。因此，IL-6可能在整个肿瘤进化的不同阶段促进肿瘤的扩展，促进细胞存活和凋亡的逃逸。揭示这些因素作用的分子机制可能为选择性操纵癌细胞对治疗的敏感性提供策略。

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