STAT3/LKB1 controls metastatic prostate cancer by regulating mTORC1/CREB pathway
| Authors | |
|---|---|
| Year of publication | 2023 |
| Type | Article in Periodical |
| Magazine / Source | Molecular Cancer |
| MU Faculty or unit | |
| Citation | PENCIK, Jan; Cecile PHILIPPE; Michaela SCHLEDERER; Emine ATAS; Matteo PECORARO; Sandra GRUND-GROESCHKE; Wen LI; Amanda TRACZ; Isabel HEIDEGGER; Sabine LAGGER; Karolína TRACHTOVÁ; Monika OBERHUBER; Ellen HEITZER; Osman AKSOY; Heidi A NEUBAUER; Bettina WINGELHOFER; Anna ORLOVA; Nadine WITZENEDER; Thomas DILLINGER; Elisa REDL; Georg GREINER; Andrea DAVID; Johnny R OSTMAN; Simone TANGERMANN; Ivana HERMANOVA; Georg SCHAEFER; Felix STERNBERG; Elena E POHL; Christina STERNBERG; Adam VARADY; Jaqueline HORVATH; Dagmar STOIBER; Tim I MALCOLM; Suzanne Dawn TURNER; Eileen E PARKES; Brigitte HANTUSCH; Gerda EGGER; Stefan ROSE-JOHN; Valeria POLI; Suneil JAIN; Chris W D ARMSTRONG; Gregor HOERMANN; Vincent GOFFIN; Fritz ABERGER; Richard MORIGGL; Arkaitz CARRACEDO; Cathal MCKINNEY; Richard D KENNEDY; Helmut KLOCKER; Michael R SPEICHER; Dean G TANG; Ali A MOAZZAMI; David M HEERY; Marcus HACKER and Lukas KENNER. STAT3/LKB1 controls metastatic prostate cancer by regulating mTORC1/CREB pathway. Molecular Cancer. LONDON: BioMed Central Ltd, 2023, vol. 22, No 1, p. 1-25. ISSN 1476-4598. Available from: https://doi.org/10.1186/s12943-023-01825-8. |
| web | https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-023-01825-8 |
| Doi | https://doi.org/10.1186/s12943-023-01825-8 |
| Keywords | STAT3; mTORC1; AR; Prostate Cancer; LKB1; AMPK; CREB; Metformin |
| Attached files | |
| 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. |
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