Pencik, Jan (Medical University of Vienna / Center for Biomarker Research in Medicine / The Salk Institute for Biological Studies) Jan Pencik Kenner, Lukas (University of Veterinary Medicine Vienna / Medical University of Vienna) Lukas Kenner Carracedo, Arkaitz (Basque Research and Technology Alliance) Arkaitz Carracedo Moriggl, Richard (University of Veterinary Medicine Vienna) Richard Moriggl Aberger, Fritz (Paris-Lodron University of Salzburg) Fritz Aberger Goffin, Vincent (Université Paris Cité) Vincent Goffin Hoermann, Gregor (Munich Leukemia Laboratory) Gregor Hoermann Armstrong, Chris W. D. (Queen's University Belfast) Chris W. D. Armstrong Jain, Suneil (Queen's University Belfast) Suneil Jain Poli, Valeria (University of Turin) Valeria Poli Rose-John, Stefan (University of Kiel) Stefan Rose-John Egger, Gerda (Medical University of Vienna / Ludwig Boltzmann Institute Applied Diagnostics) Gerda Egger Hacker, Marcus (Medical University of Vienna) Marcus Hacker Hantusch, Brigitte (Medical University of Vienna) Brigitte Hantusch Parkes, Eileen E. (University of Oxford) Eileen E. Parkes Turner, Suzanne D, (University of Cambridge / Masaryk University) Suzanne D, Turner Malcolm, Tim I. (University of Cambridge) Tim I. Malcolm Stoiber, Dagmar (Medical University of Vienna / Karl Landsteiner University of Health Sciences) Dagmar Stoiber Horvath, Jaqueline (Medical University of Vienna) Jaqueline Horvath Varady, Adam (Medical University of Vienna) Adam Varady Sternberg, Christina (University of Veterinary Medicine Vienna / Medical University of Vienna / University of Kiel ) Christina Sternberg Pohl, Elena E. (University of Veterinary Medicine Vienna) Elena E. Pohl Sternberg, Felix (University of Veterinary Medicine Vienna) Felix Sternberg Heery, David M. (University of Nottingham) David M. Heery Schäfer, Georg (Medical University Innsbruck) Georg Schäfer Hermanova, Ivana (Basque Research and Technology Alliance) Ivana Hermanova Tangermann, Simone (University of Veterinary Medicine Vienna) Simone Tangermann Östman, Johnny R. (Swedish University of Agricultural Sciences) Johnny R. Östman D'Andrea, David (Medical University of Vienna) David D'Andrea Greiner, Georg (Medical University of Vienna) Georg Greiner Redl, Elisa (Medical University of Vienna) Elisa Redl Dillinger, Thomas (Medical University of Vienna) Thomas Dillinger Witzeneder, Nadine (Medical University of Vienna) Nadine Witzeneder Orlova, Anna (University of Veterinary Medicine Vienna) Anna Orlova Moazzami, Ali A. (Swedish University of Agricultural Sciences) Ali A. Moazzami Wingelhofer, Bettina (University of Veterinary Medicine Vienna) Bettina Wingelhofer Neubauer, Heidi A. (University of Veterinary Medicine Vienna) Heidi A. Neubauer Aksoy, Osman (Medical University of Vienna / Karl Landsteiner University of Health Sciences) Osman Aksoy Heitzer, Ellen (Medical University of Graz) Ellen Heitzer Oberhuber, Monika (Center for Biomarker Research in Medicine) Monika Oberhuber Trachtová, Karolína (Medical University of Vienna / Masaryk University) Karolína Trachtová Lagger, Sabine (University of Veterinary Medicine Vienna) Sabine Lagger Heidegger, Isabel (Medical University Innsbruck) Isabel Heidegger Tracz, Amanda (Roswell Park Comprehensive Cancer Center) Amanda Tracz Li, Wen Jess (Roswell Park Comprehensive Cancer Center) Wen Jess Li Tang, Dean G. (Roswell Park Comprehensive Cancer Center) Dean G. Tang Grund-Gröschke, Sandra (Paris-Lodron University of Salzburg) Sandra Grund-Gröschke Pecoraro, Matteo (Università Della Svizzera Italiana) Matteo Pecoraro Atas, Emine (Medical University of Vienna) Emine Atas Schlederer, Michaela (Medical University of Vienna) Michaela Schlederer Philippe, Cecile (Medical University of Vienna) Cecile Philippe Speicher, Michael R. (Medical University of Graz) Michael R. Speicher Klocker, Helmut (Medical University Innsbruck) Helmut Klocker Kennedy, Richard D. (Queen's University Belfast / Almac Diagnostics) Richard D. Kennedy McKinney, Cathal (Queen's University Belfast / Almac Diagnostics) Cathal McKinney BMC 2023 Prostate cancer (PCa) is a common and fatal type of cancer in men. Metastatic PCa (mPCa) is a major factor contributing to its lethality, although the mechanisms remain poorly understood. PTEN is one of the most frequently deleted genes in mPCa. Here we show a frequent genomic co-deletion of PTEN and STAT3 in liquid biopsies of patients with mPCa. Loss of Stat3 in a Pten-null mouse prostate model leads to a reduction of LKB1/pAMPK with simultaneous activation of mTOR/CREB, resulting in metastatic disease. However, constitutive activation of Stat3 led to high LKB1/pAMPK levels and suppressed mTORC1/CREB pathway, preventing mPCa development. Metformin, one of the most widely prescribed therapeutics against type 2 diabetes, inhibits mTORC1 in liver and requires LKB1 to mediate glucose homeostasis. We find that metformin treatment of STAT3/AR-expressing PCa xenografts resulted in significantly reduced tumor growth accompanied by diminished mTORC1/CREB, AR and PSA levels. PCa xenografts with deletion of STAT3/AR nearly completely abrogated mTORC1/CREB inhibition mediated by metformin. Moreover, metformin treatment of PCa patients with high Gleason grade and type 2 diabetes resulted in undetectable mTORC1 levels and upregulated STAT3 expression. Furthermore, PCa patients with high CREB expression have worse clinical outcomes and a significantly increased risk of PCa relapse and metastatic recurrence. In summary, we have shown that STAT3 controls mPCa via LKB1/pAMPK/mTORC1/CREB signaling, which we have identified as a promising novel downstream target for the treatment of lethal mPCa. PDFDocument en 2024-02-05T09:55:28.612Z Transcription Factor; Signal Transducer; Gene-Expression; Cell-Growth; Metformin; Protein; Pten; Lkb1; Mtor; Identification 3986680 b application/pdf CC BY 4.0 International