Blockade of the LRP16-PKR-NF-κB signaling axis sensitizes colorectal carcinoma cells to DNA-damaging cytotoxic therapy.
Blockade of the LRP16-PKR-NF-κB signaling axis sensitizes colorectal carcinoma cells to DNA-damaging cytotoxic therapy.
复制标题
阻断 LRP16-PKR-NF-kappa B 信号轴使结直肠癌细胞对 DNA 损伤性细胞毒疗法敏感
作者：
Li X;Wu Z;An X;Mei Q;Bai M;Hanski L;Li X;Ahola T;Han W
肿瘤获得性治疗耐药是降低人类恶性肿瘤发病率和死亡率的一个重大障碍。在结直肠癌中，化疗敏感性和化疗耐药之间发生巨大转变的机制尚未明确。在这里，我们报道了LRP16选择性地相互作用和激活双链rna依赖性激酶（PKR），并作为支架协助PKR和IKKβ的三联物的形成，延长由dna损伤剂引起的adp核糖（PAR）依赖性核因子κB （NF-κB）转激活的聚合物，并赋予获得性化学耐药。我们还发现了一个小分子MRS2578，它显著地消除了LRP16与PKR和IKKβ的结合，将LRP16转化为死亡分子，并阻止了结肠肿瘤的发生。与单独使用每种药物相比，MRS2578与依托泊苷的结合在异种移植物中显示出协同抗肿瘤细胞毒性。我们的组合方法引入了一种策略，以提高基因毒性治疗肿瘤的疗效。大多数化疗药物通过破坏癌细胞的DNA来杀死癌细胞。细胞有对抗这种损害的系统，并帮助它们生存，在一些细胞中，这些系统有效地工作，使癌症有效地抵抗治疗。例如，一种叫做NF-κB的蛋白质可以激活各种帮助修复受损DNA的基因。然而，DNA包含在细胞核内，而NF-κB的失活形式则在细胞核外发现。那么受损的DNA是如何与NF-κ b交流并激活它们的呢？先前的研究发现，另一种名为LRP16的蛋白质存在于细胞核中，在NF-κB参与的修复过程中起着至关重要的作用。Li, Wu， An等人现在研究了从人体组织样本中提取的肠癌细胞，发现癌细胞中LRP16的含量高于周围组织的细胞。LRP16水平非常高的癌症患者受癌症影响更严重。进一步的研究表明，当DNA受损时，LRP16移出细胞核，并稳定NF-κB与其他两种蛋白质的相互作用；这种稳定性激活NF-κB。因此，LRP16似乎可以调节从受损DNA传递出细胞核的信号，从而激活NF-κB。进一步的实验表明，抗癌治疗对缺乏LRP16的癌细胞效果最好。因此，LRP16似乎有助于癌细胞对化疗引起的DNA损伤作出反应和抵抗。Li, Wu， An等人进一步发现了一种通过阻断LRP16的作用来阻止NF-κB活化的药物。与化疗药物一起使用这种药物会使细胞更容易自我毁灭。现在需要做更多的工作来开发基于新发现的药物的治疗方法，并确定DNA损伤如何激活LRP16。
Acquired therapeutic resistance by tumors is a substantial impediment to reducing the morbidity and mortality that are attributable to human malignancies. The mechanisms responsible for the dramatic shift between chemosensitivity and chemoresistance in colorectal carcinoma have not been defined. Here, we report that LRP16 selectively interacts and activates double-stranded RNA-dependent kinase (PKR), and also acts as scaffolds to assist the formation of a ternary complex of PKR and IKKβ, prolonging the polymers of ADP-ribose (PAR)-dependent nuclear factor kappa B (NF-κB) transactivation caused by DNA-damaging agents and confers acquired chemoresistance. We also identified a small molecule, MRS2578, which strikingly abrogated the binding of LRP16 to PKR and IKKβ, converting LRP16 into a death molecule and forestalling colon tumorigenesis. Inclusion of MRS2578 with etoposide, versus each drug alone, exhibited synergistic antitumor cytotoxicity in xenografts. Our combinatorial approach introduces a strategy to enhance the efficacy of genotoxicity therapies for the treatment of tumors. Most chemotherapy drugs kill cancer cells by damaging their DNA. The cells have systems to combat this damage and help them to survive, and in some cells these systems work effectively enough to make the cancer effectively resistant to the treatment. For example, a protein called NF-κB can turn on various genes that help to repair damaged DNA. However, DNA is contained the cell nucleus, whereas the inactive form of NF-κB is found outside the cell nucleus. So how does the damaged DNA communicate with – and activate – NF-κB? Previous research had found that another protein called LRP16, which resides in the cell nucleus, plays a crucial role in the repair process that NF-κB is involved in. Li, Wu, An et al. have now studied bowel cancer cells taken from human tissue samples and found that the cancerous cells contained higher levels of LRP16 than cells from the surrounding tissue. Patients with cancers containing very high levels of LRP16 were more severely affected by cancer. Further investigation revealed that when DNA is damaged, LRP16 moves out of the cell nucleus and stabilises how NF-κB interacts with two other proteins; this stabilisation activates NF-κB. LRP16 therefore appears to regulate the signal that travels out of the nucleus from the damaged DNA to activate NF-κB. Further experiments showed that anti-cancer treatments worked best on cancer cells that lacked LRP16. Thus it appears that LRP16 helps cancer cells to respond to and resist the DNA damage caused by chemotherapy. Li, Wu, An et al. went on to identify a drug that prevented the activation of NF-κB by blocking the effects of LRP16. Using this drug alongside chemotherapy drugs made the cells more likely to self-destruct. More work is now needed to develop therapies based on the newly identified drug and to establish how DNA damage activates LRP16.