2. Academic Validation
  3. HSP70-mediated mitochondrial dynamics and autophagy represent a novel vulnerability in pancreatic cancer

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

  • Cell Death Differ. 2024 May 28. doi: 10.1038/s41418-024-01310-9.
Giulia D S Ferretti # 1 2,  Colleen E Quaas # 1 2,  Irene Bertolini 3,  Alessandro Zuccotti 1 2,  Ozge Saatci 1 2,  Jennifer A Kashatus 4,  Salma Sharmin 4,  David Y Lu 3,  Adi Narayana Reddy Poli 3,  Abigail F Quesnelle 1 2,  Jezabel Rodriguez-Blanco 2 5,  Aguirre A de Cubas 2 6,  G Aaron Hobbs 2 7,  Qin Liu 3,  John P O'Bryan 2 7 8,  Joseph M Salvino 3,  David F Kashatus 4,  Ozgur Sahin 1 2,  Thibaut Barnoud 9 10
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA.
  • 2 Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA.
  • 3 Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, USA.
  • 4 Department of Microbiology, Immunology, and Cancer Biology, University of Virginia Health System, Charlottesville, VA, USA.
  • 5 Darby Children's Research Institute, Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA.
  • 6 Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA.
  • 7 Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, USA.
  • 8 Ralph H. Johnson VA Medical Center, Charleston, SC, USA.
  • 9 Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA. barnoud@musc.edu.
  • 10 Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA. barnoud@musc.edu.
  • # Contributed equally.
PMID: 38802657 DOI: 10.1038/s41418-024-01310-9
Abstract

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-162567
    HSP70抑制剂
    HSP
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