Identification of pimavanserin tartrate as a potent Ca2+-calcineurin-NFAT pathway inhibitor for glioblastoma therapy
Identification of pimavanserin tartrate as a potent Ca2+-calcineurin-NFAT pathway inhibitor for glioblastoma therapy
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酒石酸匹马范色林作为有效的 Ca2-钙调神经磷酸酶-NFAT 通路抑制剂用于胶质母细胞瘤治疗的鉴定
DOI：
10.1038/s41401-021-00724-2
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发表时间：
2021-08
影响因子：
8.2
通讯作者：
Bo Tang
中科院分区：
文献类型：
--
作者：
Zhen-zhen Liu;Xiao-ning Liu;Rui-cheng Fan;Yu-ping Jia;Qing-ke Zhang;Xin-qing Gao;Yu-qing Wang;Meng-qing Yang;Li-zhen Ji;Yong-qing Zhou;Hong-li Li;Ping Li;Bo Tang
多形性胶质母细胞瘤（GBM）是原发性脑肿瘤中最常见和最恶性的类型，95%的患者在诊断后2年内死亡。在这项研究中，旨在克服一线药物替莫唑胺（TMZ）的耐药性，我们进行了研究，以发现一种新的替代药物靶向致癌NFAT信号通路的GBM治疗。为了加速药物的临床应用，我们利用药物再利用策略来鉴定新的NFAT信号通路抑制剂。在筛选了一组93种FDA批准的具有简单结构的药物后，我们确定了pimavanserin tartrate（PIM），一种用于治疗帕金森病相关精神症状的有效5-HT 2A受体反向激动剂，对NFAT信号通路具有最有效的抑制活性。进一步的研究表明，PIM抑制STIM 1斑点的形成，以抑制钙库操纵的钙进入（SOCE）和随后的NFAT活性。在细胞内，PIM可显著抑制U87胶质母细胞瘤细胞的增殖、迁移、分裂和运动，诱导细胞阻滞于G1/S期，并促进细胞凋亡。在体内，皮下和原位胶质母细胞瘤异种移植物的生长被PIM显著抑制。无偏组学研究揭示了PIM抗肿瘤活性的新分子机制，包括抑制ATR/CDK 2/E2 F轴、MYC和AuroraA/B信号传导。有趣的是，PIM上调的基因在很大程度上与胆固醇稳态有关，这可能有助于PIM的副作用，应该给予更多的关注。我们的研究确定了钙库操纵的钙通道作为PIM的新靶点，并且是第一个系统地强调酒石酸匹莫范色林对胶质母细胞瘤的治疗潜力的研究。
Glioblastoma multiforme (GBM) is the most common and malignant type of primary brain tumor, and 95% of patients die within 2 years after diagnosis. In this study, aiming to overcome chemoresistance to the first-line drug temozolomide (TMZ), we carried out research to discover a novel alternative drug targeting the oncogenic NFAT signaling pathway for GBM therapy. To accelerate the drug’s clinical application, we took advantage of a drug repurposing strategy to identify novel NFAT signaling pathway inhibitors. After screening a set of 93 FDA-approved drugs with simple structures, we identified pimavanserin tartrate (PIM), an effective 5-HT2Areceptor inverse agonist used for the treatment of Parkinson’s disease-associated psychiatric symptoms, as having the most potent inhibitory activity against the NFAT signaling pathway. Further study revealed that PIM suppressed STIM1 puncta formation to inhibit store-operated calcium entry (SOCE) and subsequent NFAT activity. In cellula, PIM significantly suppressed the proliferation, migration, division, and motility of U87 glioblastoma cells, induced G1/S phase arrest and promoted apoptosis. In vivo, the growth of subcutaneous and orthotopic glioblastoma xenografts was markedly suppressed by PIM. Unbiased omics studies revealed the novel molecular mechanism of PIM’s antitumor activity, which included suppression of the ATR/CDK2/E2F axis, MYC, and AuroraA/B signaling. Interestingly, the genes upregulated by PIM were largely associated with cholesterol homeostasis, which may contribute to PIM’s side effects and should be given more attention. Our study identified store-operated calcium channels as novel targets of PIM and was the first to systematically highlight the therapeutic potential of pimavanserin tartrate for glioblastoma.
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影响因子：
2.4
作者：
Fernø J;Skrede S;Vik-Mo AO;Håvik B;Steen VM
通讯作者：
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影响因子：
64.5
作者：
Giordano F;Saheki Y;Idevall-Hagren O;Colombo SF;Pirruccello M;Milosevic I;Gracheva EO;Bagriantsev SN;Borgese N;De Camilli P
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通讯作者：
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影响因子：
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作者：
Marcelo A. Wood;S. McMahon;M. Cole
通讯作者：
Marcelo A. Wood;S. McMahon;M. Cole