突变型p53（Mutp53）的稳定性增加在其增强功能中起着至关重要的作用，使得参与其稳定的蛋白质成为药物干预的有希望的靶点。尽管姜黄素被认为具有抗癌作用，但其作为去泛素化酶（DUB）抑制剂在对Mutp53不稳定性的影响方面仍未被充分研究。我们的研究表明，姜黄素处理诱导了癌细胞中Mutp53而非野生型p53（WTp53）的泛素化和不稳定化。此外，蛋白酶体和溶酶体抑制剂无法扭转姜黄素的效应，说明Mutp53的不稳定可能通过另一种机制实现。有趣的是，姜黄素处理还导致Mutp53蛋白在细胞核中的聚集，而联合二巯基苏糖醇（DTT）处理则恢复了这种聚集。与姜黄素类似，一种广谱去泛素化酶抑制剂也诱导了Mutp53的聚集，暗示姜黄素可能通过抑制去泛素化酶的作用。此外，姜黄素处理抑制了突变型p53表达细胞的成团能力，诱导了细胞质液泡化和细胞死亡。总的来说，我们的研究突出了姜黄素作为一种有前景的治疗药物，用于靶向表达Mutp53的癌细胞。版权所有 © 2023 Elsevier Inc. 保留所有权利。

The increased stability of mutant p53 (Mutp53) plays a crucial role in its gain of function, making proteins involved in its stabilization promising targets for drug intervention. Although curcumin is known to exhibit anti-cancer effects, its role as a deubiquitinase (DUB) inhibitor in Mutp53 destabilization remains poorly explored. Our study demonstrates that curcumin treatment induced ubiquitination and destabilization of Mutp53 but not Wild-type p53 (WTp53) in cancer cells. Furthermore, proteasome and lysosome inhibitors failed to reverse the effect of curcumin, indicating Mutp53 destabilization is possibly via an alternate mechanism. Intriguingly, curcumin treatment also resulted in the nuclear aggregation of the Mutp53 protein, which was rescued by combined Dithiothreitol (DTT) treatment. Similar to curcumin, a broad-spectrum deubiquitinase inhibitor induced Mutp53 aggregation implying curcumin possibly acts by inhibiting deubiquitinases. Additionally, curcumin treatment inhibited colony-forming abilities, induced cytoplasmic vacuolation, and cell death selectively in Mutp53-expressing cells. Collectively, our study highlights the potential of curcumin as a promising therapeutic agent for targeting Mutp53-expressing cancer cells.Copyright © 2023 Elsevier Inc. All rights reserved.