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

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Pencik, Jan 
Philippe, Cecile 
Schlederer, Michaela 
Atas, Emine 
Pecoraro, Matteo 


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.


Acknowledgements: The authors thank Stephanie Ponti, Anna Zacher and Victoria Weissenböck for their skilful help with animal handling as well as biolution GmbH for the support with the graphical abstract.

Funder: Christian Doppler Research Association

Funder: Austrian Federal Ministry of Science, Research and Economy

Funder: National Foundation for Research, Technology and Development

Funder: Siemens Healthineers


AMPK, AR, CREB, LKB1, Metformin, Prostate Cancer, STAT3, mTORC1, Animals, Humans, Male, Mice, AMP-Activated Protein Kinases, Diabetes Mellitus, Type 2, Mechanistic Target of Rapamycin Complex 1, Metformin, Neoplasm Recurrence, Local, Prostatic Neoplasms, STAT3 Transcription Factor

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Mol Cancer

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Springer Science and Business Media LLC
Österreichischen Akademie der Wissenschaften (Max Kade)
National Institute for Cancer Research (LX22NPO5102)
Deutsche Krebshilfe (70112589)
Italian Cancer Research Association (IG 24851)
European Union Horizon 2020 Marie Sklodowska-Curie Doctoral Network grant (101072735)
BM Fonds (15142)
Margaretha Hehberger Stiftung (15142)
COMET Competence Center CBmed (FA791A0906.FFG)
Austrian Science Fund (P26011, P29251 and P 34781)
eRaDicate (101119427)
Austrian Research Promotion Agency (MicroONE)