VIB-KU Leuven Center for Brain & Disease Research, Herestraat 49, 3000 Leuven, Belgium.
Switch Laboratory, Department for Cellular and Molecular Medicine, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
Cells. 2023 Mar 21;12(6):960. doi: 10.3390/cells12060960.
In malignant cancer, excessive amounts of mutant p53 often lead to its aggregation, a feature that was recently identified as druggable. Here, we describe that induction of a heat shock-related stress response mediated by Foldlin, a small-molecule tool compound, reduces the protein levels of misfolded/aggregated mutant p53, while contact mutants or wild-type p53 remain largely unaffected. Foldlin also prevented the formation of stress-induced p53 nuclear inclusion bodies. Despite our inability to identify a specific molecular target, Foldlin also reduced protein levels of aggregating SOD1 variants. Finally, by screening a library of 778 FDA-approved compounds for their ability to reduce misfolded mutant p53, we identified the proteasome inhibitor Bortezomib with similar cellular effects as Foldlin. Overall, the induction of a cellular heat shock response seems to be an effective strategy to deal with pathological protein aggregation. It remains to be seen however, how this strategy can be translated to a clinical setting.
在恶性癌症中，过量的突变型 p53 常导致其聚集，这一特征最近被鉴定为可成药。在这里，我们描述了由小分子工具化合物 Foldlin 介导的热休克相关应激反应的诱导，降低了错误折叠/聚集的突变型 p53 的蛋白水平，而接触突变型或野生型 p53 则基本不受影响。Foldlin 还防止了应激诱导的 p53 核包含体的形成。尽管我们无法确定特定的分子靶标，但 Foldlin 也降低了聚集的 SOD1 变体的蛋白水平。最后，通过筛选 778 种 FDA 批准的化合物库，以确定其降低错误折叠突变型 p53 的能力，我们发现蛋白酶体抑制剂硼替佐米具有与 Foldlin 相似的细胞效应。总的来说，诱导细胞热休克反应似乎是应对病理性蛋白聚集的有效策略。然而，这种策略如何转化为临床环境还有待观察。
