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

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Authors	PENCIK Jan PHILIPPE Cecile SCHLEDERER Michaela ATAS Emine PECORARO Matteo GRUND-GROESCHKE Sandra LI Wen TRACZ Amanda HEIDEGGER Isabel LAGGER Sabine TRACHTOVÁ Karolína OBERHUBER Monika HEITZER Ellen AKSOY Osman NEUBAUER Heidi A WINGELHOFER Bettina ORLOVA Anna WITZENEDER Nadine DILLINGER Thomas REDL Elisa GREINER Georg DAVID Andrea OSTMAN Johnny R TANGERMANN Simone HERMANOVA Ivana SCHAEFER Georg STERNBERG Felix POHL Elena E STERNBERG Christina VARADY Adam HORVATH Jaqueline STOIBER Dagmar MALCOLM Tim I TURNER Suzanne Dawn PARKES Eileen E HANTUSCH Brigitte EGGER Gerda ROSE-JOHN Stefan POLI Valeria JAIN Suneil ARMSTRONG Chris W D HOERMANN Gregor GOFFIN Vincent ABERGER Fritz MORIGGL Richard CARRACEDO Arkaitz MCKINNEY Cathal KENNEDY Richard D KLOCKER Helmut SPEICHER Michael R TANG Dean G MOAZZAMI Ali A HEERY David M HACKER Marcus KENNER Lukas
Year of publication	2023
Type	Article in Periodical
Magazine / Source	Molecular Cancer
MU Faculty or unit	Central European Institute of Technology
Citation
Web	https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-023-01825-8
Doi	http://dx.doi.org/10.1186/s12943-023-01825-8
Keywords	STAT3; mTORC1; AR; Prostate Cancer; LKB1; AMPK; CREB; Metformin
Attached files	STAT3_LKB1_controls_metastatic_prostate_cancer_by_regulating_mTORC1_CREB_pathway.pdf
Description	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.
Related projects:	FANTOM Future of ALCL: Novel Therapies, Origins, Bio-Markers and Mechanism of resistance National institute for cancer research