The Gain-of-Function p53 R248W Mutant Promotes Migration by STAT3 Deregulation in Human Pancreatic Cancer Cells.
The Gain-of-Function p53 R248W Mutant Promotes Migration by STAT3 Deregulation in Human Pancreatic Cancer Cells.
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DOI：
10.3389/fonc.2021.642603
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发表时间：
2021
影响因子：
4.7
通讯作者：
Schulz-Heddergott R
中科院分区：
文献类型：
--
作者：
Klemke L;Fehlau CF;Winkler N;Toboll F;Singh SK;Moll UM;Schulz-Heddergott R
错义p53突变（mutp 53）发生在大约。70%的胰腺导管腺癌（PDAC）。通常，mutp 53蛋白被Hsp 90/Hsp 70/Hsp 40伴侣复合物异常稳定。值得注意的是，稳定化是特定mutp 53等位基因获得强大的新形态致癌性功能获得（GOF）的先决条件，所述功能获得主要通过增加侵袭和转移来促进实体癌中的肿瘤进展。在结直肠癌（CRC）中，我们最近确定了常见的热点突变体mutp 53 R248 Q和mutp 53 R248 W通过组成性结合和超活化STAT 3发挥GOF活性。这导致在本地CRC小鼠模型中增殖和侵袭增加，并且与患者的存活率差相关。在一系列纯合子人PDAC细胞系中比较p53错义突变的面板，我们在这里表明，类似于CRC，mutp 53 R248 W蛋白再次经历了强烈的热休克蛋白90介导的稳定性，并选择性地促进迁移。高度稳定的mutp 53可被Hsp 90抑制剂Onalbib和Ganetespib降解，并与生长抑制相关，这可能表明PDAC中靶向GOF mutp 53蛋白的治疗弱点。响应于mutp 53缺失，只有携带mutp 53 R248 W的PDAC细胞显示STAT 3去磷酸化和减少的迁移，再次表明该癌症实体中的等位基因特异性GOF，类似于CRC。此外，mutp 53 R248 W还表现出与磷酸化STAT 3形成最强的组成型复合物。选择性mutp 53 R248 W GOF通过增强STAT 3轴发出信号，这一点已得到证实，因为通过敲除或药理学抑制靶向STAT 3，表型突变mutp 53消耗并优先降低含有mutp 53 R248 W的PDAC细胞中的细胞活力和迁移。我们的研究结果证实，mutp 53 GOF活动是等位基因特异性的，可以跨越肿瘤实体。
Missense p53 mutations (mutp53) occur in approx. 70% of pancreatic ductal adenocarcinomas (PDAC). Typically, mutp53 proteins are aberrantly stabilized by Hsp90/Hsp70/Hsp40 chaperone complexes. Notably, stabilization is a precondition for specific mutp53 alleles to acquire powerful neomorphic oncogenic gain-of-functions (GOFs) that promote tumor progression in solid cancers mainly by increasing invasion and metastasis. In colorectal cancer (CRC), we recently established that the common hotspot mutants mutp53R248Q and mutp53R248W exert GOF activities by constitutively binding to and hyperactivating STAT3. This results in increased proliferation and invasion in an autochthonous CRC mouse model and correlates with poor survival in patients. Comparing a panel of p53 missense mutations in a series of homozygous human PDAC cell lines, we show here that, similar to CRC, the mutp53R248W protein again undergoes a strong Hsp90-mediated stabilization and selectively promotes migration. Highly stabilized mutp53 is degradable by the Hsp90 inhibitors Onalespib and Ganetespib, and correlates with growth suppression, possibly suggesting therapeutic vulnerabilities to target GOF mutp53 proteins in PDAC. In response to mutp53 depletion, only mutp53R248W harboring PDAC cells show STAT3 de-phosphorylation and reduced migration, again suggesting an allele-specific GOF in this cancer entity, similar to CRC. Moreover, mutp53R248W also exhibits the strongest constitutive complex formation with phosphorylated STAT3. The selective mutp53R248W GOF signals through enhancing the STAT3 axis, which was confirmed since targeting STAT3 by knockdown or pharmacological inhibition phenocopied mutp53 depletion and reduced cell viability and migration preferentially in mutp53R248W-containing PDAC cells. Our results confirm that mutp53 GOF activities are allele specific and can span across tumor entities.
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影响因子：
7.3
作者：
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