TY - JOUR
T1 - STAT3/LKB1 controls metastatic prostate cancer by regulating mTORC1/CREB pathway
AU - Pencik, Jan
AU - Philippe, Cecile
AU - Schlederer, Michaela
AU - Atas, Emine
AU - Pecoraro, Matteo
AU - Grund-Gröschke, Sandra
AU - Li, Wen Jess
AU - Tracz, Amanda
AU - Heidegger, Isabel
AU - Lagger, Sabine
AU - Trachtová, Karolína
AU - Oberhuber, Monika
AU - Heitzer, Ellen
AU - Aksoy, Osman
AU - Neubauer, Heidi A
AU - Wingelhofer, Bettina
AU - Orlova, Anna
AU - Witzeneder, Nadine
AU - Dillinger, Thomas
AU - Redl, Elisa
AU - Greiner, Georg
AU - D'Andrea, David
AU - Östman, Johnny R
AU - Tangermann, Simone
AU - Hermanova, Ivana
AU - Schäfer, Georg
AU - Sternberg, Felix
AU - Pohl, Elena E
AU - Sternberg, Christina
AU - Varady, Adam
AU - Horvath, Jaqueline
AU - Stoiber, Dagmar
AU - Malcolm, Tim I
AU - Turner, Suzanne D
AU - Parkes, Eileen E
AU - Hantusch, Brigitte
AU - Egger, Gerda
AU - Rose-John, Stefan
AU - Poli, Valeria
AU - Jain, Suneil
AU - Armstrong, Chris W D
AU - Hoermann, Gregor
AU - Goffin, Vincent
AU - Aberger, Fritz
AU - Moriggl, Richard
AU - Carracedo, Arkaitz
AU - McKinney, Cathal
AU - Kennedy, Richard D
AU - Klocker, Helmut
AU - Speicher, Michael R
AU - Tang, Dean G
AU - Moazzami, Ali A
AU - Heery, David M
AU - Hacker, Marcus
AU - Kenner, Lukas
N1 - Funding Information:
J.P. was supported by Max Kade fellowship of the Austrian Academy of Sciences and CBmed—Center for Biomarker Research. The work of S.R.J. was supported by grant Nr. 70112589 from the Deutsche Krebshilfe, Bonn, Germany. L.K. is supported by funds from a European Union Horizon 2020 Marie Sklodowska-Curie Doctoral Network grant, (FANTOM) award Project Nr. 101072735 and the eRaDicate, award Project Nr. 101119427. L.K. also acknowledges the support from MicroONE, a COMET Modul under the lead of CBmed GmbH, which is funded by the federal ministries BMK and BMDW, the provinces of Styria and Vienna, and managed by the Austrian Research Promotion Agency (FFG) within the COMET—Competence Centers for Excellent Technologies—program. Financial support was also received from the Austrian Federal Ministry of Science, Research and Economy, the National Foundation for Research, Technology and Development, and the Christian Doppler Research Association, the Siemens Healthineers, and the Austrian Science Fund (grants FWF: P26011, P29251, P34781 and International PhD Program in Translational Oncology IPPTO 59.doc.funds). L.K. was supported by the BM Fonds (n. 15142), the Margaretha Hehberger Stiftung (n. 15142), the COMET Competence Center CBmed—Center for Biomarker Research in Medicine (n. FA791A0906.FFG), and the module project microOne as well as the Christian-Doppler Lab for Applied Metabolomics, and by the Austrian Science Fund (grants FWF: P26011, P29251, and P 34781). The work of V.P. was supported by the Italian Cancer Research Association (AIRC) IG 24851 and SDT was supported by the National Institute for Cancer Research (Programme EXCELES, ID Project No. LX22NPO5102)—Funded by the European Union—Next Generation EU. Work in the Tang lab was supported, in part, by grants from the U.S National Institutes of Health (NIH) R01CA237027, R01CA240290, and grants from the U.S Department of Defense (DOD) PC220137 and PC220273. Work by F.A. was supported by the Austrian Science Fund FWF projects W1213 and P25629, the Cancer Cluster and Biomed Center Salzburg projects 20102-P1601064-FPR01-2017, 20102-F2001080FPR and 20102-F1901165KZP, and the priority program “Allergy-Cancer-Bionano Research Center” of the University of Salzburg. E.E.P. and G.E. were supported by funding from FWF Sonderforschungsbereich F83.
Publisher Copyright:
© 2023, BioMed Central Ltd., part of Springer Nature.
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
KW - Animals
KW - Humans
KW - Male
KW - Mice
KW - AMP-Activated Protein Kinases/metabolism
KW - Diabetes Mellitus, Type 2
KW - Mechanistic Target of Rapamycin Complex 1/metabolism
KW - Metformin/pharmacology
KW - Neoplasm Recurrence, Local
KW - Prostatic Neoplasms/genetics
KW - STAT3 Transcription Factor/genetics
UR - http://www.scopus.com/inward/record.url?scp=85167757546&partnerID=8YFLogxK
U2 - 10.1186/s12943-023-01825-8
DO - 10.1186/s12943-023-01825-8
M3 - Journal article
C2 - 37573301
SN - 1476-4598
VL - 22
SP - 133
JO - Molecular Cancer
JF - Molecular Cancer
IS - 1
M1 - 133
ER -