Mutant C. elegans p53 Together with Gain-of-Function GLP-1/Notch Decreases UVC-Damage-Induced Germline Cell Death but Increases PARP Inhibitor-Induced Germline Cell Death.
Mutant C. elegans p53 Together with Gain-of-Function GLP-1/Notch Decreases UVC-Damage-Induced Germline Cell Death but Increases PARP Inhibitor-Induced Germline Cell Death.
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肿瘤抑制基因TP53从线虫到人类都是保守的。在人类中，发现TP53基因在大多数癌症中发生突变，因此，p53诱导的细胞死亡途径是功能失调的。因此，确定机制和模型来测试诱导p53非依赖性癌细胞死亡的方法至关重要。小而透明的线虫秀丽隐杆线虫是一种具有生殖系干细胞肿瘤模型的完整动物，它提供了这样的机会。我们使用这个模型与一个充分研究的p53突变体，增加种系肿瘤大小，以测试诱导p53非依赖性细胞死亡的方法。在此，我们报告了两种p53独立的死亡诱导剂，核苷类似物和PARP抑制剂，能够诱导秀丽隐杆线虫种系肿瘤细胞死亡。这表明新的靶向药物可以在这个模型中测试p53非依赖性癌细胞的杀伤。TP53基因在超过50%的人类癌症中发生突变，秀丽隐杆线虫p53-1 （cep-1）基因编码同源cep-1。CEP-1被紫外线C型（UVC）诱导的DNA损伤激活，并激活诱导种系细胞凋亡的基因。UVC治疗功能获得性glp-1(ar202gf)/Notch肿瘤动物可减少种系干细胞数量（和整体肿瘤大小），而UVC治疗双突变cep-1/p53(gk138)；glp-1/Notch（ar202gf）增加DNA损伤加合物和干细胞肿瘤体积。我们比较了uvc诱导的两种不同秀丽隐杆线虫肿瘤菌株的有丝分裂干细胞死亡和动物寿命。秀丽隐杆线虫的干细胞室死亡从未被观察到，我们使用被吞噬的小干细胞，特别是绿色荧光点，来计数细胞死亡事件。我们发现UVC处理glp-1（ar202gf）动物增加了干细胞死亡并延长了寿命。然而，UVC治疗双突变cep-1/p53(gk138)；glp-1/Notch（ar202gf）动物减少干细胞死亡，增加肿瘤体积，缩短动物寿命。有药物可诱导培养的人细胞不依赖p53的细胞死亡；两个值得注意的方案是parp捕获剂替莫唑胺加塔拉唑帕尼和核苷类似物8-氨基腺苷。确定快速检测能够诱导p53非依赖性细胞死亡的药理学药物的方法是很重要的。我们测试了饲喂cep-1/p53(gk138)；glp-1/Notch（ar202gf）线虫用8-氨基腺苷或替莫唑胺加塔拉唑帕尼，发现两者都能减少肿瘤体积。这是cep-1/p53（gk138）中p53非依赖性应答的首次比较；glp-1/Notch（ar202gf）动物实验结果显示，UVC DNA损伤使肿瘤体积增大，寿命缩短，而PARP抑制使肿瘤体积减小。
The tumor suppressor gene TP53 is conserved from nematode to human. In humans the TP53 gene is found mutated in a majority of cancers and therefore, the p53-induced cell death pathway is dysfunctional. As such, it is of the utmost importance to determine mechanisms and models to test for ways to induce p53-independent cancer cell death. The small, transparent, nematode C. elegans is a whole animal with a germline stem cell tumor model that presents such an opportunity. We used this model with a well-studied p53 mutant that increases germline tumor size to test for ways to induce p53-independent cell death. Herein, we report that two p53-independent death inducers, a nucleoside analogue and a PARP inhibitor, are capable of inducing C. elegans germline tumor cell death. This suggests new targeted drugs can be tested in this model for p53-independent cancer cell killing. The TP53 gene is mutated in over 50% of human cancers, and the C. elegans p53-1 (cep-1) gene encodes the ortholog CEP-1. CEP-1 is activated by ultraviolet type C (UVC)-induced DNA damage and activates genes that induce germline apoptosis. UVC treatment of gain-of-function glp-1(ar202gf)/Notch tumorous animals reduces germline stem cell numbers (and overall tumor size), while UVC treatment of double-mutant cep-1/p53(gk138);glp-1/Notch(ar202gf) increases DNA damage adducts and stem cell tumor volume. We compared UVC-induced mitotic stem cell death and animal lifespans for the two different C. elegans tumorous strains. C. elegans stem cell compartment death has never been observed, and we used engulfed small stem cells, notable by green fluorescent puncta, to count cell death events. We found UVC treatment of glp-1(ar202gf) animals increased stem cell death and increased lifespan. However, UVC treatment of double-mutant cep-1/p53(gk138);glp-1/Notch(ar202gf) animals decreased stem cell death, increased tumor volume, and decreased animal lifespan. There are pharmacological agents that induce p53-independent cell death of human cells in culture; and two notable protocols are the PARP-trapping agents of temozolomide plus talazoparib and the nucleoside analogue 8-amino-adenosine. It is important to determine ways to rapidly test for pharmacological agents able to induce p53-independent cell death. We tested feeding cep-1/p53(gk138);glp-1/Notch(ar202gf) nematodes with either 8-amino-adenosine or temozolomide plus talazoparib and found both were able to decrease tumor volume. This is the first comparison for p53-independent responses in cep-1/p53(gk138);glp-1/Notch(ar202gf) animals and showed UVC DNA damage increased tumor volume and decreased lifespan while PARP inhibition decreased tumor volume.
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DOI：
10.1016/j.cub.2017.02.015
发表时间：
2017-03-20
期刊：
Current biology : CB
影响因子：
--
作者：
Ames K;Da Cunha DS;Gonzalez B;Konta M;Lin F;Shechter G;Starikov L;Wong S;Bülow HE;Meléndez A
通讯作者：
Meléndez A
影响因子：
56.9
作者：
Arantes-Oliveira, N;Apfeld, J;Kenyon, C
通讯作者：
Kenyon, C
影响因子：
12.4
作者：
Derry, W. B.;Bierings, R.;Rothman, J. H.
通讯作者：
Rothman, J. H.
影响因子：
3.7
作者：
Hoffman S;Martin D;Meléndez A;Bargonetti J
通讯作者：
Bargonetti J
影响因子：
8
作者：
Levine AJ
通讯作者：
Levine AJ