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一种新型的TAp73抑制性化合物可对抗胶质母细胞瘤干细胞的干性特征。

A novel TAp73-inhibitory compound counteracts stemness features of glioblastoma stem cells.

作者信息

Villoch-Fernandez Javier, Martínez-García Nicole, Martín-López Marta, Maeso-Alonso Laura, López-Ferreras Lorena, Vazquez-Jimenez Alberto, Muñoz-Hidalgo Lisandra, Garcia-Romero Noemí, Sanchez Jose María, Fernandez Antonio, Ayuso-Sacido Angel, Marques Margarita M, Marin Maria C

机构信息

Instituto de Biomedicina y Departamento de Biología Molecular, Universidad de León, Spain.

Instituto de Biomedicina y Departamento de Producción Animal, Universidad de León, Spain.

出版信息

Mol Oncol. 2025 Mar;19(3):852-877. doi: 10.1002/1878-0261.13694. Epub 2024 Aug 1.

DOI:10.1002/1878-0261.13694
PMID:39090849
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11887682/
Abstract

Glioblastoma (GB) is the most common and fatal type of primary malignant brain tumor for which effective therapeutics are still lacking. GB stem cells, with tumor-initiating and self-renewal capacity, are mostly responsible for GB malignancy, representing a crucial target for therapies. The TP73 gene, which is highly expressed in GB, gives rise to the TAp73 isoform, a pleiotropic protein that regulates neural stem cell biology; however, its role in cancer has been highly controversial. We inactivated TP73 in human GB stem cells and revealed that TAp73 is required for their stemness potential, acting as a regulator of the transcriptional stemness signatures, highlighting TAp73 as a possible therapeutic target. As proof of concept, we identified a novel natural compound with TAp73-inhibitory capacity, which was highly effective against GB stem cells. The treatment reduced GB stem cell-invasion capacity and stem features, at least in part by TAp73 repression. Our data are consistent with a novel paradigm in which hijacking of p73-regulated neurodevelopmental programs, including neural stemness, might sustain tumor progression, pointing out TAp73 as a therapeutic strategy for GB.

摘要

胶质母细胞瘤（GB）是最常见且致命的原发性恶性脑肿瘤类型，目前仍缺乏有效的治疗方法。GB干细胞具有肿瘤起始和自我更新能力，是GB恶性肿瘤的主要成因，是治疗的关键靶点。TP73基因在GB中高度表达，可产生TAp73异构体，这是一种调节神经干细胞生物学的多效性蛋白；然而其在癌症中的作用一直备受争议。我们使人类GB干细胞中的TP73失活，发现TAp73是其干性潜能所必需的，作为转录干性特征的调节因子，凸显了TAp73作为一个可能的治疗靶点。作为概念验证，我们鉴定出一种具有TAp73抑制能力的新型天然化合物，它对GB干细胞非常有效。该治疗至少部分通过抑制TAp73降低了GB干细胞的侵袭能力和干细胞特征。我们的数据与一种新的模式一致，即劫持包括神经干细胞干性在内的p73调控的神经发育程序可能维持肿瘤进展，指出TAp73是GB的一种治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1d7f/11887682/594bef500da7/MOL2-19-852-g005.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1d7f/11887682/594bef500da7/MOL2-19-852-g005.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1d7f/11887682/544818f788bf/MOL2-19-852-g004.jpg
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本文引用的文献

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Acta Neuropathol Commun. 2023 Jun 24;11(1):104. doi: 10.1186/s40478-023-01605-x.
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p53-independent tumor suppression by cell-cycle arrest via CREB/ATF transcription factor OASIS.通过 CREB/ATF 转录因子 OASIS 引起的细胞周期停滞实现 p53 非依赖性肿瘤抑制。
Cell Rep. 2023 May 30;42(5):112479. doi: 10.1016/j.celrep.2023.112479. Epub 2023 May 12.
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ΔNp63/p73 drive metastatic colonization by controlling a regenerative epithelial stem cell program in quasi-mesenchymal cancer stem cells.
ΔNp63/p73 通过控制准间质肿瘤干细胞中的再生上皮干细胞程序来驱动转移性定植。
Dev Cell. 2022 Dec 19;57(24):2714-2730.e8. doi: 10.1016/j.devcel.2022.11.015.
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p73 is required for vessel integrity controlling endothelial junctional dynamics through Angiomotin.p73 通过血管生成素调节蛋白（Angiomotin）维持血管完整性，调控内皮细胞连接的动态变化。
Cell Mol Life Sci. 2022 Oct 1;79(10):535. doi: 10.1007/s00018-022-04560-3.
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An update on the molecular biology of glioblastoma, with clinical implications and progress in its treatment.胶质母细胞瘤的分子生物学最新进展及其治疗的临床意义和进展。
Cancer Commun (Lond). 2022 Nov;42(11):1083-1111. doi: 10.1002/cac2.12361. Epub 2022 Sep 21.
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p73 isoforms meet evolution of metastasis.p73亚型与转移的演变相关。
Cancer Metastasis Rev. 2022 Dec;41(4):853-869. doi: 10.1007/s10555-022-10057-z. Epub 2022 Aug 11.
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ATF6 prevents DNA damage and cell death in colon cancer cells undergoing ER stress.活化转录因子6可预防内质网应激状态下结肠癌细胞中的DNA损伤和细胞死亡。
Cell Death Discov. 2022 Jun 25;8(1):295. doi: 10.1038/s41420-022-01085-3.
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[TAp73α is Upregulated in the Most Common Human Cancers].[TAp73α在最常见的人类癌症中上调]
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