Abstract：
According to the World Health Organization in 2022, 2.3 million women were diagnosed with breast cancer. Investigating the interaction networks between Bcl-2-associated athanogene (Bag)-1 and other chaperone proteins may further the current understanding of the regulation of protein homeostasis in breast cancer cells and contribute to the development of treatment options. The present study aimed to determine the interactions between Bag-1 and heat shock proteins (HSPs); namely, HSP90, HSP70 and HSP27, to elucidate their role in promoting heat shock factor-1 (HSF1)-dependent survival of breast cancer cells. HER2-negative (MCF-7) and HER2-positive (BT-474) cell lines were used to examine the impact of Bag-1 expression on HSF1 and HSPs. We demonstrated that Bag-1 overexpression promoted HER2 expression in breast cancer cells, thereby resulting in the concurrent constitutive activation of the HSF1-HSP axis. The activation of HSP results in the stabilization of several tumor-promoting HSP clients such as AKT, mTOR and HSF1 itself, which substantially accelerates tumor development. Our results suggest that Bag-1 can modulate the chaperone activity of HSPs, such as HSP27, by directly or indirectly regulating the phosphorylation of HSF1. This modulation of chaperone activity can influence the activation of genes involved in cellular homeostasis, thereby protecting cells against stress.
摘要：
根据世界卫生组织在2022年的数据，有230万女性被诊断出患有乳腺癌。研究Bcl-2相关基因基因（Bag）-1和其他分子伴侣蛋白之间的相互作用网络可能进一步了解乳腺癌细胞中蛋白质稳态的调节，并有助于治疗方案的发展。本研究旨在确定Bag-1与热休克蛋白（HSPs）之间的相互作用；即HSP90，HSP70和HSP27，以阐明它们在促进热休克因子-1（HSF1）依赖性乳腺癌细胞存活中的作用。使用HER2阴性(MCF-7)和HER2阳性(BT-474)细胞系来检查Bag-1表达对HSF1和HSP的影响。我们证明Bag-1过表达促进乳腺癌细胞中HER2的表达，从而导致HSF1-HSP轴的同时组成型激活。HSP的激活导致几个促进肿瘤的HSP客户端的稳定，如AKT，MTOR和HSF1本身，这大大加速了肿瘤的发展。我们的结果表明，Bag-1可以调节HSP的伴侣活性，例如HSP27,通过直接或间接调节HSF1的磷酸化。这种伴侣活性的调节可以影响参与细胞稳态的基因的激活，从而保护细胞免受压力。
