Titel (eng)

STAT3/LKB1 controls metastatic prostate cancer by regulating mTORC1/CREB pathway

Autor*in

Jan Pencik   Medical University of Vienna / Center for Biomarker Research in Medicine / The Salk Institute for Biological Studies

Lukas Kenner   University of Veterinary Medicine Vienna / Medical University of Vienna

Marcus Hacker   Medical University of Vienna

David M. Heery   University of Nottingham

Ali A. Moazzami   Swedish University of Agricultural Sciences

Dean G. Tang   Roswell Park Comprehensive Cancer Center

Michael R. Speicher   Medical University of Graz

Helmut Klocker   Medical University Innsbruck

Richard D. Kennedy   Queen's University Belfast / Almac Diagnostics

Cathal McKinney   Queen's University Belfast / Almac Diagnostics

Arkaitz Carracedo   Basque Research and Technology Alliance

Richard Moriggl   University of Veterinary Medicine Vienna

Fritz Aberger   Paris-Lodron University of Salzburg

Vincent Goffin   Université Paris Cité

Gregor Hoermann   Munich Leukemia Laboratory

Chris W. D. Armstrong   Queen's University Belfast

Suneil Jain   Queen's University Belfast

Valeria Poli   University of Turin

Stefan Rose-John   University of Kiel

Gerda Egger   Medical University of Vienna / Ludwig Boltzmann Institute Applied Diagnostics

Brigitte Hantusch   Medical University of Vienna

Eileen E. Parkes   University of Oxford

Suzanne D, Turner   University of Cambridge / Masaryk University

Tim I. Malcolm   University of Cambridge

Dagmar Stoiber   Medical University of Vienna / Karl Landsteiner University of Health Sciences

Jaqueline Horvath   Medical University of Vienna

Adam Varady   Medical University of Vienna

Christina Sternberg   University of Veterinary Medicine Vienna / Medical University of Vienna / University of Kiel

Elena E. Pohl   University of Veterinary Medicine Vienna

Felix Sternberg   University of Veterinary Medicine Vienna

Georg Schäfer   Medical University Innsbruck

Ivana Hermanova   Basque Research and Technology Alliance

Simone Tangermann   University of Veterinary Medicine Vienna

Johnny R. Östman   Swedish University of Agricultural Sciences

David D'Andrea   Medical University of Vienna

Georg Greiner   Medical University of Vienna

Elisa Redl   Medical University of Vienna

Thomas Dillinger   Medical University of Vienna

Nadine Witzeneder   Medical University of Vienna

Anna Orlova   University of Veterinary Medicine Vienna

Bettina Wingelhofer   University of Veterinary Medicine Vienna

Heidi A. Neubauer   University of Veterinary Medicine Vienna

Osman Aksoy   Medical University of Vienna / Karl Landsteiner University of Health Sciences

Ellen Heitzer   Medical University of Graz

Monika Oberhuber   Center for Biomarker Research in Medicine

Karolína Trachtová   Medical University of Vienna / Masaryk University

Sabine Lagger   University of Veterinary Medicine Vienna

Isabel Heidegger   Medical University Innsbruck

Amanda Tracz   Roswell Park Comprehensive Cancer Center

Wen Jess Li   Roswell Park Comprehensive Cancer Center

Sandra Grund-Gröschke   Paris-Lodron University of Salzburg

Matteo Pecoraro   Università Della Svizzera Italiana

Emine Atas   Medical University of Vienna

Michaela Schlederer   Medical University of Vienna

Cecile Philippe   Medical University of Vienna

Verlag

BMC

Beschreibung (eng)

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.

Sprache des Objekts

Englisch

Datum

2023

Rechte

Dieses Werk bzw. dieser Inhalt steht unter einer
CC BY 4.0 - Creative Commons Namensnennung 4.0 International Lizenz.

CC BY 4.0 International

http://creativecommons.org/licenses/by/4.0/

Klassifikation

Transcription Factor; Signal Transducer; Gene-Expression; Cell-Growth; Metformin; Protein; Pten; Lkb1; Mtor; Identification

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