PDF(Pubmed)
Abstract：
Our recent work has uncovered a novel function of HSPA8 as an amyloidase, capable of dismantling the RHIM-containing protein fibrils to suppress necroptosis. However, the impact of HSPA8 inhibitors on cancer regression via necroptosis remains unexplored. In this study, we conducted a comprehensive investigation to assess the potential of HSPA8 inhibitors in enhancing necroptosis both in vitro and in vivo. Our findings indicate that pharmacologic inhibition of HSPA8, achieved either through VER (VER-155008) targeting the nucleotide binding domain or pifithrin-μ targeting the substrate binding domain of HSPA8, significantly potentiates necroptosis induced by diverse treatments in cellular assays. These inhibitors effectively disrupt the binding of HSPA8 to the RHIM protein, impeding its regulatory function on RHIM amyloid formation. Importantly, HSPA8 inhibitors significantly enhanced cancer cell sensitivity to microtubule-targeting agents (MTAs) in vitro, while reversing chemoresistance and facilitating tumor regression by augmenting necroptosis in vivo. Our findings suggest a promising therapeutic approach to cancer through necroptosis modulation via HSPA8 targeting, particularly in combination with MTA drugs for enhanced treatment efficacy.
摘要：
我们最近的工作发现了HSPA8作为淀粉样蛋白酶的新功能，能够拆除含RHIM的蛋白原纤维以抑制坏死。然而,HSPA8抑制剂通过坏死性凋亡对癌症消退的影响仍未被研究.在这项研究中,我们进行了一项全面的研究,以评估HSPA8抑制剂在体外和体内增强坏死的潜力.我们的发现表明，通过靶向NBD结构域的VER（VER-155008）或靶向HSPA8的SBD结构域的PES（吡虫啉-μ）实现的HSPA8的药理学抑制显着增强了细胞测定中多种治疗方法诱导的坏死。这些抑制剂有效地破坏HSPA8与RHIM蛋白的结合，阻碍其对RHIM淀粉样蛋白形成的调节功能。重要的是,HSPA8抑制剂在体外显着增强了癌细胞对微管靶向剂（MTA）的敏感性，同时通过体内增加坏死来逆转化疗耐药并促进肿瘤消退。我们的研究结果表明，通过HSPA8靶向通过坏死调节来治疗癌症是一种有希望的治疗方法，特别是与MTA药物组合以增强治疗功效。
