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A Novel AMPK Inhibitor Sensitizes Pancreatic Cancer Cells to Ferroptosis Induction.
Schneider, Carolin; Hilbert, Jorina; Genevaux, Franziska; Höfer, Stefanie; Krauß, Lukas; Schicktanz, Felix; Contreras, Constanza Tapia; Jansari, Shaishavi; Papargyriou, Aristeidis; Richter, Thorsten; Alfayomy, Abdallah M; Falcomatà, Chiara; Schneeweis, Christian; Orben, Felix; Öllinger, Ruppert; Wegwitz, Florian; Boshnakovska, Angela; Rehling, Peter; Müller, Denise; Ströbel, Philipp; Ellenrieder, Volker; Conradi, Lena; Hessmann, Elisabeth; Ghadimi, Michael; Grade, Marian; Wirth, Matthias; Steiger, Katja; Rad, Roland; Kuster, Bernhard; Sippl, Wolfgang; Reichert, Maximilian; Saur, Dieter; Schneider, Günter.
Afiliação
  • Schneider C; Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37075, Göttingen, Germany.
  • Hilbert J; Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37075, Göttingen, Germany.
  • Genevaux F; Medical Clinic and Polyclinic II, Klinikum rechts der Isar, Technical University of Munich, 81675, Munich, Germany.
  • Höfer S; Proteomics and Bioanalytics, Department of Molecular Life Sciences, School of Life Sciences, Technical University of Munich, 85354, Freising, Germany.
  • Krauß L; Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37075, Göttingen, Germany.
  • Schicktanz F; Institute of Pathology, Technical University of Munich, 81675, Munich, Germany.
  • Contreras CT; Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37075, Göttingen, Germany.
  • Jansari S; Department of Gynecology and Obstetrics, University Medical Center Göttingen, Göttingen, Germany.
  • Papargyriou A; Medical Clinic and Polyclinic II, Klinikum rechts der Isar, Technical University of Munich, 81675, Munich, Germany.
  • Richter T; Institute of Stem Cell Research, Helmholtz Zentrum Muenchen, D-85764, Neuherberg, Germany.
  • Alfayomy AM; Translational Pancreatic Research Cancer Center, Medical Clinic and Polyclinic II, Klinikum rechts der Isar, Technical University of Munich, 81675, Munich, Germany.
  • Falcomatà C; Center for Organoid Systems (COS), Technical University of Munich, 85747, Garching, Germany.
  • Schneeweis C; Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37075, Göttingen, Germany.
  • Orben F; Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther University Halle-Wittenberg, 06120, Halle (Saale), Germany.
  • Öllinger R; Department of Pharmaceutical Chemistry, Al-Azhar University, Assiut, 71524, Egypt.
  • Wegwitz F; Institute for Translational Cancer Research and Experimental Cancer Therapy, Technical University Munich, 81675, Munich, Germany.
  • Boshnakovska A; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Rehling P; Institute for Translational Cancer Research and Experimental Cancer Therapy, Technical University Munich, 81675, Munich, Germany.
  • Müller D; Medical Clinic and Polyclinic II, Klinikum rechts der Isar, Technical University of Munich, 81675, Munich, Germany.
  • Ströbel P; Institute of Molecular Oncology and Functional Genomics, TUM School of Medicine, Technical University of Munich, 81675, Munich, Germany.
  • Ellenrieder V; Department of Gynecology and Obstetrics, University Medical Center Göttingen, Göttingen, Germany.
  • Conradi L; Department of Cellular Biochemistry, University Medical Center, 37073, Göttingen, Germany.
  • Hessmann E; Department of Cellular Biochemistry, University Medical Center, 37073, Göttingen, Germany.
  • Ghadimi M; Max Planck Institute for Biophysical Chemistry, 37077, Göttingen, Germany.
  • Grade M; Institute of Pathology, University Medical Center, 37075, Göttingen, Germany.
  • Wirth M; Institute of Pathology, University Medical Center, 37075, Göttingen, Germany.
  • Steiger K; Clinical Research Unit 5002, KFO5002, University Medical Center Göttingen, 37075, Göttingen, Germany.
  • Rad R; CCC-N (Comprehensive Cancer Center Lower Saxony), 37075, Göttingen, Germany.
  • Kuster B; Clinical Research Unit 5002, KFO5002, University Medical Center Göttingen, 37075, Göttingen, Germany.
  • Sippl W; CCC-N (Comprehensive Cancer Center Lower Saxony), 37075, Göttingen, Germany.
  • Reichert M; Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, 37075, Göttingen, Germany.
  • Saur D; Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37075, Göttingen, Germany.
  • Schneider G; Clinical Research Unit 5002, KFO5002, University Medical Center Göttingen, 37075, Göttingen, Germany.
Adv Sci (Weinh) ; 11(31): e2307695, 2024 Aug.
Article em En | MEDLINE | ID: mdl-38885414
ABSTRACT
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Pancreáticas / Proteínas Quinases Ativadas por AMP / Ferroptose Limite: Animals / Humans Idioma: En Revista: Adv Sci (Weinh) Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Alemanha País de publicação: Alemanha

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Pancreáticas / Proteínas Quinases Ativadas por AMP / Ferroptose Limite: Animals / Humans Idioma: En Revista: Adv Sci (Weinh) Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Alemanha País de publicação: Alemanha