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

Varování

Publikace nespadá pod Filozofickou fakultu, ale pod Středoevropský technologický institut. Oficiální stránka publikace je na webu muni.cz.

Autoři	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
Rok publikování	2023
Druh	Článek v odborném periodiku
Časopis / Zdroj	Molecular Cancer
Fakulta / Pracoviště MU	Středoevropský technologický institut
Citace
www	https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-023-01825-8
Doi	http://dx.doi.org/10.1186/s12943-023-01825-8
Klíčová slova	STAT3; mTORC1; AR; Prostate Cancer; LKB1; AMPK; CREB; Metformin
Přiložené soubory	STAT3_LKB1_controls_metastatic_prostate_cancer_by_regulating_mTORC1_CREB_pathway.pdf
Popis	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.
Související projekty:	FANTOM Future of ALCL: Novel Therapies, Origins, Bio-Markers and Mechanism of resistance Národní ústav pro výzkum rakoviny