Department of Pharmacology and Biochemistry, School of Pharmacy Fudan University, Shanghai 201203, China.
School of Pharmacy, Nantong University, 19 Qixiu Road, Nantong, Jiangsu Province 226001, China.
Biochem Pharmacol. 2019 Apr;162:142-153. doi: 10.1016/j.bcp.2018.10.021. Epub 2018 Oct 21.
Cancer cells are continuously challenged by adverse environmental stress and adopt diverse strategies to survive. Hsp70 plays pivotal roles in invasion, migration, drug resistance, and the survival of tumor cells. Hsp70 functions as molecular chaperone to protect tumor cells from stress-induced cell death. Hsp70 acetylation alters its chaperone activity in cell death pathways, but its relevance in the process of cell death and the underlying mechanisms involved are not well understood. In this study, we demonstrated that vincristine induces mitophagy via the disruption of Hsp70 binding with Sirt2, leading to Hsp70 acetylation at K126 and elevated sequestration of Bcl2 by Hsp70 for autophagosome creation. Acetylation at K126 significantly changes the physiological function of Hsp70 compared to acetylation at other sites. It also attenuates the protein folding and renaturation function of Hsp70 by altering the binding co-chaperones. In addition, acetylation at K126 inhibits Hsp70-mediated tumor cell invasion and migration, and the binding of Hsp70 to AIF1 and Apaf1 for promoting mitochondrial-mediated apoptosis. In conclusion, this study describes the molecular mechanism of vincristine induction of cell apoptosis and mitophagy via ablation of Sirt2 induced Hsp70 acetylation at K126 in MDA-MB-231 cells.
癌细胞不断受到不利环境压力的挑战，并采取多种策略来生存。Hsp70 在肿瘤细胞的侵袭、迁移、耐药性和存活中发挥着关键作用。Hsp70 作为分子伴侣，可保护肿瘤细胞免受应激诱导的细胞死亡。Hsp70 的乙酰化改变了其在细胞死亡途径中的伴侣活性，但它在细胞死亡过程中的相关性及其涉及的潜在机制尚不清楚。在这项研究中，我们证明长春新碱通过破坏 Hsp70 与 Sirt2 的结合，诱导有丝分裂自噬，导致 Hsp70 在 K126 上乙酰化，并通过 Hsp70 将 Bcl2 隔离到自噬体中，从而促进有丝分裂自噬。与其他位点的乙酰化相比，K126 上的乙酰化显著改变了 Hsp70 的生理功能。它还通过改变结合共伴侣来削弱 Hsp70 的蛋白折叠和复性功能。此外，K126 上的乙酰化抑制了 Hsp70 介导的肿瘤细胞侵袭和迁移，以及 Hsp70 与 AIF1 和 Apaf1 的结合，从而促进了线粒体介导的细胞凋亡。总之，本研究描述了长春新碱通过 Sirt2 诱导的 Hsp70 在 K126 上的乙酰化来诱导细胞凋亡和有丝分裂自噬的分子机制，在 MDA-MB-231 细胞中。
