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聚（ADP-核糖）聚合酶 1（PARP1）抑制通过促进 ezrin 磷酸化促进骨肉瘤的肺转移。

Poly (ADP-ribose) polymerase 1 (PARP1) inhibition promotes pulmonary metastasis of osteosarcoma by boosting ezrin phosphorylation.

机构信息

Shum Yiu Foon Sum Bik Chuen Memorial Centre for Cancer and Inflammation Research (CCIR), School of Chinese Medicine, Hong Kong Baptist University, 999077, Hong Kong SAR, China.

Law Sau Fai Institute for Advancing Translational Medicine in Bone & Joint Diseases, Hong Kong Baptist University, 999077, Hong Kong SAR, China.

出版信息

Int J Biol Sci. 2022 Jan 9;18(3):1238-1253. doi: 10.7150/ijbs.58784. eCollection 2022.

DOI:10.7150/ijbs.58784
PMID:35173550
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8771856/
Abstract

Due to the large proportion of BRCA deficiency and chromosomal instability in OS patients, poly (ADP-ribose) polymerase inhibitors (PARPi) could be an effective strategy for anti-OS therapy. In two orthotopic OS mouse models, we discovered that although PARPi had inhibitory effect on the growth of the orthotopic OS tumors regardless of BRCA deficiency, the treatment of PARPi essentially aggravated the pulmonary metastasis of OS in both models. A protein playing a crucial role in OS metastasis, ezrin, was identified as an interactive protein for PARP1. The phosphorylation of ezrin was significantly promoted during PARP inhibition. Besides the traditional function of phosphorylated ezrin at plasma membrane, we newly identified its nuclear speckle localization and its function with mRNA export. Ezrin knockdown or phosphorylation inhibition could partially rescue PARPi induced metastasis. Collectively, we unveiled a new mechanism for PARP-involved OS metastasis, which proposed a novel combinational therapy strategy using PARP and ezrin inhibitors for future OS treatment.

摘要

由于 OS 患者中 BRCA 缺陷和染色体不稳定性的比例较大，聚（ADP-核糖）聚合酶抑制剂（PARPi）可能成为抗 OS 治疗的有效策略。在两种原位 OS 小鼠模型中，我们发现，尽管 PARPi 对 BRCA 缺陷与否的原位 OS 肿瘤的生长均有抑制作用，但 PARPi 的治疗实质上加剧了两种模型中的 OS 肺转移。一种在 OS 转移中起关键作用的蛋白质 ezrin 被鉴定为 PARP1 的相互作用蛋白。PARP 抑制期间 ezrin 的磷酸化显著增强。除了磷酸化 ezrin 在质膜上的传统功能外，我们还新鉴定了其核斑点定位及其与 mRNA 输出的功能。ezrin 的敲低或磷酸化抑制可部分挽救 PARPi 诱导的转移。总之，我们揭示了 PARP 参与的 OS 转移的新机制，为未来的 OS 治疗提出了使用 PARP 和 ezrin 抑制剂的新联合治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba31/8771856/5277625bef32/ijbsv18p1238g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba31/8771856/f7d0e5d256e8/ijbsv18p1238g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba31/8771856/f4284a3d03d1/ijbsv18p1238g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba31/8771856/e2046e125937/ijbsv18p1238g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba31/8771856/67d1efa60e43/ijbsv18p1238g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba31/8771856/b39e5358a9db/ijbsv18p1238g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba31/8771856/69bdda0ce757/ijbsv18p1238g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba31/8771856/5277625bef32/ijbsv18p1238g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba31/8771856/f7d0e5d256e8/ijbsv18p1238g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba31/8771856/f4284a3d03d1/ijbsv18p1238g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba31/8771856/e2046e125937/ijbsv18p1238g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba31/8771856/67d1efa60e43/ijbsv18p1238g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba31/8771856/b39e5358a9db/ijbsv18p1238g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba31/8771856/69bdda0ce757/ijbsv18p1238g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba31/8771856/5277625bef32/ijbsv18p1238g007.jpg

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