Department of Cell and Cancer Biology, College of Medicine and Life Sciences, The University of Toledo, Toledo, OH 43614, USA.
Int J Mol Sci. 2024 Oct 30;25(21):11657. doi: 10.3390/ijms252111657.
Copper is crucial for many physiological processes across mammalian cells, including energy metabolism, neurotransmitter synthesis, and antioxidant defense mechanisms. However, excessive copper levels can lead to cellular toxicity and "cuproptosis", a form of programmed cell death characterized by the accumulation of copper within mitochondria. Tumor cells are less sensitive to this toxicity than normal cells, the mechanism for which remains unclear. We address this important issue by exploring the role of heat shock factor 1 (HSF1), a transcription factor that is highly expressed across several types of cancer and has a crucial role in tumor survival, in protecting against copper-mediated cytotoxicity. Using pancreatic ductal adenocarcinoma cells, we show that excessive copper triggers a proteotoxic stress response (PSR), activating HSF1 and that overexpressing HSF1 diminishes intracellular copper accumulation and prevents excessive copper-induced cell death and amyloid fibrils formation, highlighting HSF1's role in preserving proteasomal integrity. Copper treatment decreases the lipoylation of dihydrolipoamide S-acetyltransferase (DLAT), an enzyme necessary for cuproptosis, induces DLAT oligomerization, and induces insoluble DLAT formation, which is suppressed by overexpressing HSF1, in addition to enhancing the interaction between HSF1 and DLAT. Our findings uncover how HSF1 protects against copper-induced damage in cancer cells and thus represents a novel therapeutic target for enhancing copper-mediated cancer cell death.
铜对于哺乳动物细胞中的许多生理过程至关重要，包括能量代谢、神经递质合成和抗氧化防御机制。然而，过量的铜水平会导致细胞毒性和“铜死亡”，这是一种程序性细胞死亡的形式，其特征是在线粒体中积累铜。肿瘤细胞比正常细胞对这种毒性的敏感性较低，其机制尚不清楚。我们通过研究热休克因子 1（HSF1）在保护铜介导的细胞毒性方面的作用来解决这个重要问题。HSF1 是一种在多种类型的癌症中高度表达的转录因子，在肿瘤存活中起着至关重要的作用。我们使用胰腺导管腺癌细胞表明，过量的铜会引发蛋白毒性应激反应（PSR），激活 HSF1，而过表达 HSF1 则会减少细胞内铜的积累，防止过量铜诱导的细胞死亡和淀粉样纤维的形成，突出了 HSF1 在维持蛋白酶体完整性方面的作用。铜处理会降低二氢乳酰脱氢酶 S-乙酰转移酶（DLAT）的脂酰化，DLAT 是铜死亡所必需的酶，会诱导 DLAT 寡聚化，并诱导不溶性 DLAT 的形成，而过表达 HSF1 会抑制这种形成，同时还会增强 HSF1 和 DLAT 之间的相互作用。我们的发现揭示了 HSF1 如何在癌细胞中保护其免受铜诱导的损伤，因此代表了一种增强铜介导的癌细胞死亡的新的治疗靶点。
