A Novel AMPK Inhibitor Sensitizes Pancreatic Cancer Cells to Ferroptosis Induction.

AMPK ferroptosis pancreatic cancer

Journal

Advanced science (Weinheim, Baden-Wurttemberg, Germany)
ISSN: 2198-3844
Titre abrégé: Adv Sci (Weinh)
Pays: Germany
ID NLM: 101664569

Informations de publication

Date de publication:
17 Jun 2024
Historique:
revised: 12 04 2024
received: 13 10 2023
medline: 17 6 2024
pubmed: 17 6 2024
entrez: 17 6 2024
Statut: aheadofprint

Résumé

Cancer cells must develop strategies to adapt to the dynamically changing stresses caused by intrinsic or extrinsic processes, or therapeutic agents. Metabolic adaptability is crucial to mitigate such challenges. Considering metabolism as a central node of adaptability, it is focused on an energy sensor, the AMP-activated protein kinase (AMPK). In a subtype of pancreatic ductal adenocarcinoma (PDAC) elevated AMPK expression and phosphorylation is identified. Using drug repurposing that combined screening experiments and chemoproteomic affinity profiling, it is identified and characterized PF-3758309, initially developed as an inhibitor of PAK4, as an AMPK inhibitor. PF-3758309 shows activity in pre-clinical PDAC models, including primary patient-derived organoids. Genetic loss-of-function experiments showed that AMPK limits the induction of ferroptosis, and consequently, PF-3758309 treatment restores the sensitivity toward ferroptosis inducers. The work established a chemical scaffold for the development of specific AMPK-targeting compounds and deciphered the framework for the development of AMPK inhibitor-based combination therapies tailored for PDAC.

Identifiants

pubmed: 38885414
doi: 10.1002/advs.202307695
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

e2307695

Subventions

Organisme : German Cancer Aid
ID : 70113760
Organisme : German Cancer Aid
ID : 70115444
Organisme : German Cancer Aid
ID : 111273
Organisme : Wilhelm-Sander-Stiftung
ID : 2023.027.1
Organisme : Wilhelm-Sander-Stiftung
ID : 2022.074.1
Organisme : Deutsche Forschungsgemeinschaft
ID : SCHN 959/6-1
Organisme : Deutsche Forschungsgemeinschaft
ID : SCHN959/7-1
Organisme : Deutsche Forschungsgemeinschaft
ID : SCHN959/8-1
Organisme : Deutsche Forschungsgemeinschaft
ID : SCHN 959/3-2
Organisme : Deutsche Forschungsgemeinschaft
ID : RE 3723/4-1
Organisme : Deutsche Forschungsgemeinschaft
ID : RE 3723/6-1
Organisme : Deutsche Forschungsgemeinschaft
ID : ID329628492(SFB1321)
Organisme : Deutsche Forschungsgemeinschaft
ID : KFO5002
Organisme : Deutsche Forschungsgemeinschaft
ID : WI 6148/1-1
Organisme : Bavarian Ministry of Economic Affairs
ID : LSM-2104-0017
Organisme : Bavarian Ministry of Economic Affairs
ID : BMBF
Organisme : Bavarian Ministry of Economic Affairs
ID : 01KD2206P
Organisme : Bavarian Ministry of Economic Affairs
ID : 13N16450
Organisme : Bavarian Ministry of Economic Affairs
ID : 01KD2208B
Organisme : DKTK (German Cancer Consortium) Strategic Initiative Organoid Platform

Informations de copyright

© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.

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Auteurs

Carolin Schneider (C)

Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37075, Göttingen, Germany.

Jorina Hilbert (J)

Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37075, Göttingen, Germany.

Franziska Genevaux (F)

Medical Clinic and Polyclinic II, Klinikum rechts der Isar, Technical University of Munich, 81675, Munich, Germany.

Stefanie Höfer (S)

Proteomics and Bioanalytics, Department of Molecular Life Sciences, School of Life Sciences, Technical University of Munich, 85354, Freising, Germany.

Lukas Krauß (L)

Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37075, Göttingen, Germany.

Felix Schicktanz (F)

Institute of Pathology, Technical University of Munich, 81675, Munich, Germany.

Constanza Tapia Contreras (CT)

Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37075, Göttingen, Germany.

Shaishavi Jansari (S)

Department of Gynecology and Obstetrics, University Medical Center Göttingen, Göttingen, Germany.

Aristeidis Papargyriou (A)

Medical Clinic and Polyclinic II, Klinikum rechts der Isar, Technical University of Munich, 81675, Munich, Germany.
Institute of Stem Cell Research, Helmholtz Zentrum Muenchen, D-85764, Neuherberg, Germany.
Translational Pancreatic Research Cancer Center, Medical Clinic and Polyclinic II, Klinikum rechts der Isar, Technical University of Munich, 81675, Munich, Germany.
Center for Organoid Systems (COS), Technical University of Munich, 85747, Garching, Germany.

Thorsten Richter (T)

Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37075, Göttingen, Germany.

Abdallah M Alfayomy (AM)

Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther University Halle-Wittenberg, 06120, Halle (Saale), Germany.
Department of Pharmaceutical Chemistry, Al-Azhar University, Assiut, 71524, Egypt.

Chiara Falcomatà (C)

Institute for Translational Cancer Research and Experimental Cancer Therapy, Technical University Munich, 81675, Munich, Germany.
Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Christian Schneeweis (C)

Institute for Translational Cancer Research and Experimental Cancer Therapy, Technical University Munich, 81675, Munich, Germany.

Felix Orben (F)

Medical Clinic and Polyclinic II, Klinikum rechts der Isar, Technical University of Munich, 81675, Munich, Germany.

Ruppert Öllinger (R)

Institute of Molecular Oncology and Functional Genomics, TUM School of Medicine, Technical University of Munich, 81675, Munich, Germany.

Florian Wegwitz (F)

Department of Gynecology and Obstetrics, University Medical Center Göttingen, Göttingen, Germany.

Angela Boshnakovska (A)

Department of Cellular Biochemistry, University Medical Center, 37073, Göttingen, Germany.

Peter Rehling (P)

Department of Cellular Biochemistry, University Medical Center, 37073, Göttingen, Germany.
Max Planck Institute for Biophysical Chemistry, 37077, Göttingen, Germany.

Denise Müller (D)

Institute of Pathology, University Medical Center, 37075, Göttingen, Germany.

Philipp Ströbel (P)

Institute of Pathology, University Medical Center, 37075, Göttingen, Germany.
Clinical Research Unit 5002, KFO5002, University Medical Center Göttingen, 37075, Göttingen, Germany.
CCC-N (Comprehensive Cancer Center Lower Saxony), 37075, Göttingen, Germany.

Volker Ellenrieder (V)

Clinical Research Unit 5002, KFO5002, University Medical Center Göttingen, 37075, Göttingen, Germany.
CCC-N (Comprehensive Cancer Center Lower Saxony), 37075, Göttingen, Germany.
Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, 37075, Göttingen, Germany.

Lena Conradi (L)

Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37075, Göttingen, Germany.
Clinical Research Unit 5002, KFO5002, University Medical Center Göttingen, 37075, Göttingen, Germany.
CCC-N (Comprehensive Cancer Center Lower Saxony), 37075, Göttingen, Germany.

Elisabeth Hessmann (E)

Clinical Research Unit 5002, KFO5002, University Medical Center Göttingen, 37075, Göttingen, Germany.
CCC-N (Comprehensive Cancer Center Lower Saxony), 37075, Göttingen, Germany.
Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, 37075, Göttingen, Germany.

Michael Ghadimi (M)

Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37075, Göttingen, Germany.
CCC-N (Comprehensive Cancer Center Lower Saxony), 37075, Göttingen, Germany.

Marian Grade (M)

Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37075, Göttingen, Germany.
CCC-N (Comprehensive Cancer Center Lower Saxony), 37075, Göttingen, Germany.

Matthias Wirth (M)

Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37075, Göttingen, Germany.
Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 12203, Berlin, Germany.

Katja Steiger (K)

Institute of Pathology, Technical University of Munich, 81675, Munich, Germany.
German Cancer Consortium (DKTK), partner site Munich, a partnership between DKFZ and University Hospital Klinikum rechts der Isar, 81675, München, Germany.

Roland Rad (R)

Institute of Molecular Oncology and Functional Genomics, TUM School of Medicine, Technical University of Munich, 81675, Munich, Germany.
German Cancer Consortium (DKTK), partner site Munich, a partnership between DKFZ and University Hospital Klinikum rechts der Isar, 81675, München, Germany.

Bernhard Kuster (B)

Proteomics and Bioanalytics, Department of Molecular Life Sciences, School of Life Sciences, Technical University of Munich, 85354, Freising, Germany.
German Cancer Consortium (DKTK), partner site Munich, a partnership between DKFZ and University Hospital Klinikum rechts der Isar, 81675, München, Germany.

Wolfgang Sippl (W)

Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther University Halle-Wittenberg, 06120, Halle (Saale), Germany.

Maximilian Reichert (M)

Medical Clinic and Polyclinic II, Klinikum rechts der Isar, Technical University of Munich, 81675, Munich, Germany.
Translational Pancreatic Research Cancer Center, Medical Clinic and Polyclinic II, Klinikum rechts der Isar, Technical University of Munich, 81675, Munich, Germany.
Center for Organoid Systems (COS), Technical University of Munich, 85747, Garching, Germany.
German Cancer Consortium (DKTK), partner site Munich, a partnership between DKFZ and University Hospital Klinikum rechts der Isar, 81675, München, Germany.
Center for Protein Assemblies (CPA), Technical University of Munich, 85747, Garching, Germany.

Dieter Saur (D)

Institute for Translational Cancer Research and Experimental Cancer Therapy, Technical University Munich, 81675, Munich, Germany.
German Cancer Consortium (DKTK), partner site Munich, a partnership between DKFZ and University Hospital Klinikum rechts der Isar, 81675, München, Germany.

Günter Schneider (G)

Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37075, Göttingen, Germany.
Institute for Translational Cancer Research and Experimental Cancer Therapy, Technical University Munich, 81675, Munich, Germany.
Clinical Research Unit 5002, KFO5002, University Medical Center Göttingen, 37075, Göttingen, Germany.
CCC-N (Comprehensive Cancer Center Lower Saxony), 37075, Göttingen, Germany.

Classifications MeSH