胰腺导管腺癌 (PDAC) 是最常见的胰腺癌类型，也是最致命的癌症之一，治疗选择有限。热休克蛋白 70 (HSP70) 的过度表达是癌症的一个标志，与侵袭性疾病和较差的临床结果密切相关。然而，HSP70 使肿瘤细胞在持续应激条件下茁壮成长的潜在机制尚未得到充分描述。在这里，我们报告说，在所有分析的癌症中，相对于正常组织，PDAC 的 HSP70 表达最高。此外，HSP70 表达与肿瘤分级相关，并且在转移性 PDAC 中进一步增强。我们发现 HSP70 的遗传或治疗消融会改变线粒体亚细胞定位，损害线粒体动力学，并促进线粒体肿胀以诱导细胞凋亡。从机制上讲，我们发现靶向 HSP70 会抑制 PTEN 诱导的激酶 1 (PINK1) 介导的动力相关蛋白 1 (DRP1) 的磷酸化。 HSP70 抑制剂 AP-4-139B 作为单一药物治疗 PDAC 的原发性和转移性小鼠模型是有效的。此外，我们证明 HSP70 抑制可促进 AMP 激活蛋白激酶 (AMPK) 介导的 Beclin-1 磷酸化，Beclin-1 是自噬流的关键调节因子。因此，我们发现自噬抑制剂羟氯喹（HCQ）增强了AP-4-139B介导体内抗肿瘤活性的能力。总的来说，我们的结果表明 HSP70 是肿瘤发生的多功能驱动因素，协调线粒体动力学和自噬。此外，这些发现支持同时抑制 HSP70 和自噬作为 HSP70 驱动的 PDAC 的新型治疗方法的基本原理。© 2024。作者。

Pancreatic ductal adenocarcinoma (PDAC), the most prevalent type of pancreatic cancer, is one of the deadliest forms of cancer with limited therapy options. Overexpression of the heat shock protein 70 (HSP70) is a hallmark of cancer that is strongly associated with aggressive disease and worse clinical outcomes. However, the underlying mechanisms by which HSP70 allows tumor cells to thrive under conditions of continuous stress have not been fully described. Here, we report that PDAC has the highest expression of HSP70 relative to normal tissue across all cancers analyzed. Furthermore, HSP70 expression is associated with tumor grade and is further enhanced in metastatic PDAC. We show that genetic or therapeutic ablation of HSP70 alters mitochondrial subcellular localization, impairs mitochondrial dynamics, and promotes mitochondrial swelling to induce apoptosis. Mechanistically, we find that targeting HSP70 suppresses the PTEN-induced kinase 1 (PINK1) mediated phosphorylation of dynamin-related protein 1 (DRP1). Treatment with the HSP70 inhibitor AP-4-139B was efficacious as a single agent in primary and metastatic mouse models of PDAC. In addition, we demonstrate that HSP70 inhibition promotes the AMP-activated protein kinase (AMPK) mediated phosphorylation of Beclin-1, a key regulator of autophagic flux. Accordingly, we find that the autophagy inhibitor hydroxychloroquine (HCQ) enhances the ability of AP-4-139B to mediate anti-tumor activity in vivo. Collectively, our results suggest that HSP70 is a multi-functional driver of tumorigenesis that orchestrates mitochondrial dynamics and autophagy. Moreover, these findings support the rationale for concurrent inhibition of HSP70 and autophagy as a novel therapeutic approach for HSP70-driven PDAC.© 2024. The Author(s).