HSP70-mediated mitochondrial dynamics and autophagy represent a novel vulnerability in pancreatic cancer

作者：Giulia D. S. Ferretti, Colleen E. Quaas, Irene Bertolini, Alessandro Zuccotti, Özge Saatci, Jennifer A. Kashatus, Salma Sharmin, David Y. Lu, Adi Narayana Reddy Poli, Abigail F. Quesnelle, Jezabel Rodríguez‐Blanco, Aguirre A. de Cubas, G. Aaron Hobbs, Qin Liu, John P. O’Bryan, Joseph M. Salvino, David F. Kashatus, Özgür Şahin, Thibaut Barnoud · 发表于：Cell Death and Differentiation · 年份：2024 · DOI：10.1038/s41418-024-01310-9 · 被引用次数：51 · 研究领域：Autophagy in Disease and Therapy、Heat shock proteins research、Endoplasmic Reticulum Stress and Disease

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 result...