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

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  • Additional Information
    • Source:
      Publisher: Nature Publishing Group Country of Publication: England NLM ID: 9437445 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5403 (Electronic) Linking ISSN: 13509047 NLM ISO Abbreviation: Cell Death Differ Subsets: MEDLINE
    • Publication Information:
      Publication: <2003->: London : Nature Publishing Group
      Original Publication: London : Edward Arnold, c1994-
    • Subject Terms:
      Mitochondrial Dynamics*/drug effects ; HSP70 Heat-Shock Proteins*/metabolism ; Pancreatic Neoplasms*/metabolism ; Pancreatic Neoplasms*/pathology ; Pancreatic Neoplasms*/drug therapy ; Autophagy*/drug effects ; Carcinoma, Pancreatic Ductal*/metabolism ; Carcinoma, Pancreatic Ductal*/pathology ; Carcinoma, Pancreatic Ductal*/drug therapy; Humans ; Animals ; Mice ; Cell Line, Tumor ; Mitochondria/metabolism ; Mitochondria/drug effects ; Protein Kinases/metabolism
    • 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.
      (© 2024. The Author(s).)
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    • Grant Information:
      R01 CA212608 United States CA NCI NIH HHS; P30 DK123704 United States DK NIDDK NIH HHS; T32 CA193201 United States CA NCI NIH HHS; I01 BX002095 United States BX BLRD VA; S10 OD030245 United States CD ODCDC CDC HHS; 1I01BX002095 U.S. Department of Veterans Affairs (Department of Veterans Affairs); P20 GM130457 United States GM NIGMS NIH HHS; 22-20-HOBB Pancreatic Cancer Action Network (Pancreatic Cancer Action Network, Inc.); R01 CA267101 United States CA NCI NIH HHS; PF-181301-TBG American Cancer Society (American Cancer Society, Inc.); K01 CA245231 United States CA NCI NIH HHS; S10 OD030245 United States OD NIH HHS; R00 CA241367 United States CA NCI NIH HHS; P30 CA138313 United States CA NCI NIH HHS; P30 CA010815 United States CA NCI NIH HHS; U54 CA274499 United States CA NCI NIH HHS; R01 CA251374 United States CA NCI NIH HHS; K01 NS119351 United States NS NINDS NIH HHS
    • Accession Number:
      0 (HSP70 Heat-Shock Proteins)
      EC 2.7.11.1 (PTEN-induced putative kinase)
      EC 2.7.- (Protein Kinases)
    • Publication Date:
      Date Created: 20240527 Date Completed: 20240711 Latest Revision: 20241210
    • Publication Date:
      20241210
    • Accession Number:
      PMC11239841
    • Accession Number:
      10.1038/s41418-024-01310-9
    • Accession Number:
      38802657