更新于：2024-11-01

PP2A x CIP2A

更新于：2024-11-01

基本信息

关联

项与 PP2A x CIP2A 相关的药物

TD-19

靶点

CIP2A x PP2A

作用机制

CIP2A inhibitors [+1]

在研机构

国立台湾大学 [+3]

原研机构

National Taiwan University Hospital

在研适应症

三阴性乳腺癌 [+2]

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 PP2A x CIP2A 相关的临床结果

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100 项与 PP2A x CIP2A 相关的转化医学

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0 项与 PP2A x CIP2A 相关的专利（医药）

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287

项与 PP2A x CIP2A 相关的文献（医药）

2024-10-01·Journal of Biological Chemistry

PP2A activation overcomes leptomeningeal dissemination in Group 3 medulloblastoma

Article

作者: Kang, Kyung-Don ; Stewart, Jerry E ; Quinn, Colin H. ; Beierle, Elizabeth A. ; Bownes, Laura V. ; Beierle, Andee M ; Nazam, Nazia ; Stewart, Jerry E. ; Erwin, Michael H. ; Beierle, Andee M. ; Butey, Swatika ; Erwin, Michael H ; Julson, Janet R ; Mroczek-Musulman, Elizabeth ; Bownes, Laura V ; Julson, Janet R. ; Ohlmeyer, Michael ; Beierle, Elizabeth A ; Quinn, Colin H

Leptomeningeal dissemination (LMD) is the primary cause of treatment failure in children with Group 3 medulloblastoma (MB). Building on our previous work on protein phosphatase 2A (PP2A) activation in MB, here we present pre-clinical and molecular data on the effects of two novel classes of PP2A activators on disease processes of LMD in Group 3 MB. The PP2A activators employed in this study are ATUX-6156 and ATUX-6954 (diarylmethylcycloamine sulfonylureas), and ATUX-1215 and ATUX-5800 (diarylmethyl-4-aminotetrahydropyran-sulfonamides). Treatment with these compounds led to suppression of the endogenous PP2A inhibitor, cancerous inhibitor of PP2A (CIP2A), enhanced phosphatase activity (10-60%), and reduced MB viability, migration, and invasion, prerequisites for MB cells to access the cerebrospinal fluid, affecting the initiation stage of LMD. PP2A activator treatment of MB cells led to apoptosis mediated via caspase 9/PARP signaling due to decreased phosphorylation of Bad, impeding the dispersal stage of LMD. Cell proliferation and LMD-driving cellular traits and molecules pertinent to the third stage, colonization, were also affected. Treatment with ATUX-1215 or ATUX-5800 prevented LMD in an intraventricular murine model of MB, possibly mediated by disruption of the CCL2-CCR2 axis by altered NF-kB phosphorylation via disrupted AKT signaling. The present investigation offers proof-of-principle data for PP2A-based reactivation therapy for Group 3 MB and provides the first indications that PP2A reactivation may challenge the current paradigm in targeting the 3-stage process of MB LMD. Further investigations of PP2A activators are warranted as these compounds may prove beneficial as therapeutics for MB.

2024-10-01·MedComm

Penfluridol inhibits melanoma growth and metastasis through enhancing von Hippel‒Lindau tumor suppressor‐mediated cancerous inhibitor of protein phosphatase 2A (CIP2A) degradation

Article

作者: Li, Jiao ; Xu, Fuyan ; Pu, Wenchen ; Ai, Min ; Qi, Yucheng ; Yang, Yang ; Ming, Yue ; Xia, Yong ; Sun, Qingxiang ; Li, Cong ; Zhang, Tingting ; Li, Zhang ; Yuan, Zhu ; Peng, Yong ; Xu, Xiaomin

AbstractMelanoma's high metastatic potential, especially to the brain, poses significant challenges to patient survival. The blood‒brain barrier (BBB) is a major obstacle to the effective treatment of melanoma brain metastases. We screened antipsychotic drugs capable of crossing the BBB and identified penfluridol (PF) as the most active candidate. PF reduced melanoma cell viability and induced apoptosis. In animal models, PF effectively inhibited melanoma growth and metastasis to the lung and brain. Using immunoprecipitation combined with high‐resolution mass spectrometry, and other techniques such as drug affinity responsive target stability, we identified CIP2A as a direct binding protein of PF. CIP2A is highly expressed in melanoma and its metastases, and is linked to poor prognosis. PF can restore Protein Phosphatase 2A activity by promoting CIP2A degradation, thereby inhibiting several key oncogenic pathways, including AKT and c‐Myc. Additionally, von Hippel‒Lindau (VHL) is the endogenous E3 ligase for CIP2A, and PF enhances the interaction between VHL and CIP2A, promoting the ubiquitin‒proteasome degradation of CIP2A, thereby inhibiting melanoma growth and metastasis. Overall, this study not only suggests PF's potential in treating melanoma and its brain metastases but also highlights CIP2A degradation as a therapeutic strategy for melanoma.

2024-08-01·Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

Loss of function variant in CIP2A associated with female infertility with early embryonic arrest and fragmentation

Article

作者: Liu, Zhenxing ; Zhang, Xianqin ; Zou, Tingting ; Zhu, Lixia ; Jin, Lei ; Liu, Huihui ; Hou, Meiqi ; Zhou, Xiaopei ; Xi, Qingsong

BACKGROUNDEarly embryonic arrest and fragmentation (EEAF) is a common cause of female infertility, but the genetic causes remain to be largely unknown. CIP2A encodes the cellular inhibitor of PP2A, playing a crucial role in mitosis and mouse oocyte meiosis.METHODSExome sequencing and Sanger sequencing were performed to identify candidate causative genes in patients with EEAF. The pathogenicity of the CIP2A variant was assessed and confirmed in cultured cell lines and human oocytes through Western blotting, semi-quantitative RT-PCR, TUNEL staining, and fluorescence localization analysis.FINDINGSWe identified CIP2A (c.1510C > T, p.L504F) as a novel disease-causing gene in human EEAF from a consanguineous family. L504 is highly conserved throughout evolution. The CIP2A variant (c.1510C > T, p.L504F) reduced the expression level of the mutant CIP2A protein, leading to the abnormal aggregation of mutant CIP2A protein and cell apoptosis. Abnormal aggregation of CIP2A protein and chromosomal dispersion occurred in the patient's oocytes and early embryos. We further replicated the patient phenotype by knockdown CIP2A in human oocytes. Additionally, CIP2A deficiency resulted in decreased levels of phosphorylated ERK1/2.INTERPRETATIONWe first found that the CIP2A loss-of-function variant associate with female infertility characterized by EEAF. Our findings suggest the uniqueness and importance of CIP2A gene in human oocyte and early embryo development.FUNDINGThis work was supported by National Key Research and Development Program of China (2023YFC2706302), the National Natural Science Foundation of China (81000079, 81170165, and 81870959), the HUST Academic Frontier Youth Team (2016QYTD02), and the Key Research of Huazhong University of Science and Technology, Tongji Hospital (2022A20).

项与 PP2A x CIP2A 相关的新闻（医药）

2024-02-10

·生物探索

Cell Discov | 中国医学科学院周光飙/王桂珍/刘雨桃发现非小细胞肺癌治疗新策略

引言肿瘤细胞通常被认为线粒体呼吸有缺陷，但人类非小细胞肺癌(NSCLC)肿瘤组织相对于邻近的良性肺有增强的葡萄糖氧化。2024年2月6日，中国医学科学院/北京协和医学院周光飙、王桂珍及刘雨桃共同通讯在Cell Discovery (IF 34)在线发表题为“CIP2A induces PKM2 tetramer formation and oxidative phosphorylation in non-small cell lung cancer”的研究论文，该研究表明癌蛋白蛋白磷酸酶2A (CIP2A)抑制糖酵解并促进非小细胞肺癌细胞的氧化代谢。CIP2A结合到丙酮酸激酶M2 (PKM2)并诱导PKM2四聚体的形成，丝氨酸287作为PKM2二聚体-四聚体转换所必需的新磷酸化位点。CIP2A将PKM2重定向到线粒体，通过在苏氨酸69位点磷酸化Bcl2，导致Bcl2的上调。临床发现肿瘤组织中CIP2A水平与磷酸化PKM2 S287水平呈正相关。以CIP2A为靶点的化合物与糖酵解抑制剂协同抑制细胞体外和体内增殖。这些结果表明CIP2A通过促进四聚体PKM2的形成来促进氧化磷酸化，并且靶向CIP2A和糖酵解在非小细胞肺癌中具有治疗潜力。癌细胞表现出Warburg效应(有氧糖酵解)，通常被认为线粒体呼吸有缺陷。然而，最近的证据表明，癌细胞也保留线粒体呼吸，这使得细胞增殖。通过术中13C-葡萄糖在体内输注，人类非小细胞肺癌(NSCLC)肿瘤相对于邻近良性肺具有增强的葡萄糖氧化。与此一致的是，小鼠肺癌肿瘤的生长需要电子传递链氧化泛醇，而癌细胞中缺乏线粒体复合物III会损害肿瘤的生长。与正常肺组织相比，KRAS驱动的小鼠肺肿瘤增加了葡萄糖对三羧酸(TCA)循环的贡献，而丙酮酸的线粒体代谢对于体内肿瘤的形成至关重要。在细胞水平上，肺腺癌细胞线粒体复合体I和复合体II呼吸活性显著增加；胆管癌干细胞(CSCs)具有更有效的呼吸表型，并依赖线粒体氧化代谢来维持干细胞，而胰腺癌CSCs依赖于氧化磷酸化(OXPHOS)，代谢可塑性非常有限。在三阴性乳腺癌中，一些癌蛋白，如C-JUN，可以抑制糖酵解途径，而MYC和MCL1通过增加OXPHOS和活性氧的产生，共同维持CSC对化疗的耐药性。然而，氧化代谢在癌细胞中的作用和机制仍有待阐明。蛋白磷酸酶2A (PP2A)是一种丝氨酸/苏氨酸磷酸酶，由催化C亚基、结构α亚基和调节/可变B亚基12组成，它的能力被PP2A的癌症抑制剂(CIP2A)抑制，CIP2A是一种多功能癌蛋白，以前被称为KIAA1524或p9013-15。CIP2A与100多种蛋白质相互作用，并参与许多信号通路。CIP2A结合并阻止c-Myc的蛋白水解降解，并与DNA拓扑异构酶II结合蛋白1 (TopBP1)相互作用，以维护染色体稳定性，并使粉碎的染色体在有丝分裂进入时聚集。CIP2A调节细胞周期进程，促进恶性转化，并使癌细胞耐药。CIP2A在70%以上的实体或血液恶性肿瘤中过表达，并与患者预后不良相关。小鼠CIP2A缺乏可导致对DMBA诱导的基底样乳腺癌形成的抗性，抑制CIP2A可诱导细胞周期阻滞，促进细胞凋亡或细胞衰老，并在体外和体内显示出治疗效果。因此，CIP2A在癌变过程中发挥着重要的作用，更多地研究其生物学功能可能有助于开发CIP2A抑制剂来治疗癌症。CIP2A诱导PKM2构象变化和生物学功能的示意图（Credit: Cell Discovery）一些报道表明CIP2A与代谢重编程有关。在慢性髓性白血病细胞系K562中，CIP2A可增强线粒体呼吸功能。在人视网膜色素上皮RPE1细胞中，CIP2A的缺失使代谢转向糖酵解途径，增加糖酵解相关基因的表达，并下调TCA周期相关基因。然而，CIP2A在代谢重编程中的作用机制及其与代谢酶的潜在相互作用有待进一步研究。该研究检测了CIP2A在代谢重编程中的作用和作用机制，发现CIP2A通过诱导PKM2寡聚化促进NSCLC细胞的氧化代谢，其中S287是决定二聚体转换的关键氨基酸。CIP2A通过PKM2介导的Bcl2苏氨酸磷酸化上调Bcl2 (T)。体外和体内实验表明，CIP2A抑制剂联合糖酵解抑制剂对NSCLC细胞的抑制作用增强。该研究揭示了CIP2A在调节PKM2寡聚化中的新功能，并为非小细胞肺癌的治疗提供了潜力。原文链接https://www.nature.com/articles/s41421-023-00633-0责编|探索君排版|探索君文章来源|“iNature”End往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文Science最新发布：全世界最前沿的125个科学问题热文Nature | 2024年值得关注的七项技术热文Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文Nature | 癌症与神经系统的致命舞蹈

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