Zeitschriftenaufsatz
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2023
STAT3/LKB1 controls metastatic prostate cancer by regulating mTORC1/CREB pathway
Autor:in
Pencik, Jan; Philippe, Cecile; Schlederer, Michaela; Atas, Emine; Pecoraro, M.; Grund-Groeschke, S.; Li, Wen (Jess); Tracz, Amanda; Heidegger, Isabel; Lagger, Sabine; Trachtova, Karolina; Oberhuber, Monika; Heitzer, Ellen; Aksoy, Osman; Neubauer, Heidi; Wingelhofer, B.; Orlova, Anna; Witzeneder, Nadine; Dillinger, Thomas; Redl, Elisa; Greiner, G.; D'andrea, David; Ostman, Johnny R.; Tangermann, Simone; Hermanova, Ivana; Schafer, Georg; Sternberg, Felix; Pohl, Elena; Sternberg, Christina; Varady, Adam; Horvath, J.; Stoiber, Dagmar; Malcolm, Tim I.; Turner, Suzanne; Parkes, Eileen; Hantusch, Brigitte; Egger, Gerda; Rose-John, Stefan; Poli, Valeria; Jain, Suneil; Armstrong, Chris; Hoermann, Gregor; GOFFIN, Vincent; Aberger, Fritz; Moriggl, Richard; Carracedo, Arkaitz; McKinney, C.; Kennedy, R.; Klocker, Helmut; Speicher, Michael; Tang, Dean G.; Moazzami, Ali; Heery, David M.; Hacker, Marcus; Kenner, Lukas
Publikationen als Autor:in / Herausgeber:in der Vetmeduni
Journal
Abstrakt
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.
Schlagwörter
STAT3; mTORC1; AR; Prostate Cancer; LKB1; AMPK; CREB; Metformin
Dokumententyp
Originalarbeit
CC Lizenz
CCBY
Open Access Type
Gold
10.1186/s12943-023-01825-8
WoS ID
PubMed ID
Repository Phaidra