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

Jan Pencik, Cecile Philippe, Michaela Schlederer, Emine Atas, Matteo Pecoraro, Sandra Grund-Gröschke, Wen Jess Li, Amanda Tracz, Isabel Heidegger, Sabine Lagger, Karolína Trachtová, Monika Oberhuber, Ellen Heitzer, Osman Aksoy, Heidi A Neubauer, Bettina Wingelhofer, Anna Orlova, Nadine Witzeneder, Thomas Dillinger, Elisa RedlGeorg Greiner, David D'Andrea, Johnny R Östman, Simone Tangermann, Ivana Hermanova, Georg Schäfer, Felix Sternberg, Elena E Pohl, Christina Sternberg, Adam Varady, Jaqueline Horvath, Dagmar Stoiber, Tim I Malcolm, Suzanne D Turner, Eileen E Parkes, Brigitte Hantusch, Gerda Egger, Stefan Rose-John, Valeria Poli, Suneil Jain, Chris W D Armstrong, Gregor Hoermann, Vincent Goffin, Fritz Aberger, Richard Moriggl, Arkaitz Carracedo, Cathal McKinney, Richard D Kennedy, Helmut Klocker, Michael R Speicher, Dean G Tang, Ali A Moazzami, David M Heery, Marcus Hacker, Lukas Kenner

Research output: Journal article (peer-reviewed)Journal article

3 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number133
Pages (from-to)133
JournalMolecular Cancer
Volume22
Issue number1
DOIs
Publication statusPublished - Dec 2023

Keywords

  • Animals
  • Humans
  • Male
  • Mice
  • AMP-Activated Protein Kinases/metabolism
  • Diabetes Mellitus, Type 2
  • Mechanistic Target of Rapamycin Complex 1/metabolism
  • Metformin/pharmacology
  • Neoplasm Recurrence, Local
  • Prostatic Neoplasms/genetics
  • STAT3 Transcription Factor/genetics

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