Pharmacological Inhibition of PARP6 Triggers Multipolar Spindle Formation and Elicits Therapeutic Effects in Breast Cancer
Pharmacological Inhibition of PARP6 Triggers Multipolar Spindle Formation and Elicits Therapeutic Effects in Breast Cancer
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DOI：
10.1158/0008-5472.can-18-1362
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发表时间：
2018-12-01
期刊：
影响因子：
11.2
通讯作者：
Chen, Huawei
中科院分区：
文献类型：
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作者：
Wang, Zebin;Grosskurth, Shaun E.;Chen, Huawei
PARP蛋白是一类具有不同细胞功能的翻译后修饰酶。靶向PARP已被证明在临床上是有效的，但对PARP抑制的治疗潜力的探索仅限于靶向产生PARP的聚(ADP-核糖)，包括PARP1/2/3和tankyrase。产生PARP的单(ADP-核糖)的癌症相关功能，包括PARP6，在很大程度上仍未确定。在这里，我们报告了一种新的针对PARP6的治疗策略，该策略使用了第一个已报道的PARP6抑制剂。通过筛选一组PARP化合物诱导有丝分裂缺陷的能力，我们发现PARP6抑制和诱导多极纺锤体(MPS)形成之间存在强烈的相关性，而多极纺锤体的形成被PARP6基因敲除。AZ0108是一种具有良好药代动力学特征的PARP6抑制剂，它能有效地诱导MPS表型，在体外导致部分乳腺癌细胞的凋亡，并在体内产生抗肿瘤作用。此外，Chk1被鉴定为PARP6的特异性底物，并通过酶分析和质谱分析进一步证实。此外，当AZ0108抑制乳腺癌细胞中Chk1的修饰时，我们观察到p-S345 Chk1的显著上调伴随着有丝分裂信号的缺陷。综上所述，这些结果通过抑制PARP6确立了概念验证的抗肿瘤效果，并突出了PARP6通过直接ADP核糖化Chk1并调节其活性来维持中心体完整性的新功能。意义：这些发现描述了一种新的PARP6抑制剂，并确定了PARP6在调节乳腺癌细胞中Chk1激活的新功能。(C)2018年AACR。
PARP proteins represent a class of post-translational modification enzymes with diverse cellular functions. Targeting PARPs has proven to be efficacious clinically, but exploration of the therapeutic potential of PARP inhibition has been limited to targeting poly(ADP-ribose) generating PARP, including PARP1/2/3 and tankyrases. The cancer-related functions of mono(ADP-ribose) generating PARP, including PARP6, remain largely uncharacterized. Here, we report a novel therapeutic strategy targeting PARP6 using the first reported PARP6 inhibitors. By screening a collection of PARP compounds for their ability to induce mitotic defects, we uncovered a robust correlation between PARP6 inhibition and induction of multipolar spindle (MPS) formation, which was phenocopied by PARP6 knockdown. Treatment with AZ0108, a PARP6 inhibitor with a favorable pharmacokinetic profile, potently induced theMPSphenotype, leading to apoptosis in a subset of breast cancer cells in vitro and antitumor effects in vivo. In addition, Chk1 was identified as a specific substrate of PARP6 and was further confirmed by enzymatic assays and by mass spectrometry. Furthermor e, when modification of Chk1 was inhibited with AZ0108 in breast cancer cells, we observed marked upregulation of p-S345 Chk1 accompanied by defects in mitotic signaling. Together, these results establish proof-of-concept antitumor efficacy through PARP6 inhibition and highlight a novel function of PARP6 in maintaining centrosome integrity via direct ADP-ribosylation of Chk1 and modulation of its activity.Significance: These findings describe a new inhibitor of PARP6 and identify a novel function of PARP6 in regulating activation of Chk1 in breast cancer cells. (C) 2018 AACR.