| Autor: |
Jan Pencik, Cecile Philippe, Michaela Schlederer, Matteo Pecoraro, Sandra Grund-Gröschke, Wen Jess 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, David D’Andrea, Johnny R. Östman, Simone Tangermann, Ivana Hermanova, Georg Schäfer, Adam Varady, Jaqueline Horvath, Dagmar Stoiber, Timothy I. Malcolm, Suzanne D. Turner, Eileen 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, Matthias Mann, Ali A. Moazzami, David M. Heery, Marcus Hacker, Lukas Kenner |
| Rok vydání: |
2022 |
| Popis: |
Prostate cancer (PCa) lethality is driven by its progression to a metastatic castration-resistant state, yet the signaling mechanisms underlying metastatic spread remain unknown. Here we show that STAT3 converges with the LKB1/mTORC1 and CREB to control metastatic disease in PCa mouse models. Unexpectedly, STAT3 was found to be upregulated in diabetic PCa patients undergoing metformin therapy with a concomitant reduction in mTORC1 expression. In preclinical mouse models of PCa, genetic ablation or activation of STAT3 had opposing effects on LKB1/AMPK/mTORC1- dependent tumorigenesis. Using genetic and pharmacological approaches, we identified LKB1 as a direct STAT3 target while repressing CREB. Furthermore, PCa patients with high CREB expression had inferior clinical outcome with significantly increased risk of disease and metastatic recurrence. We observe that castration state lowers STAT3 abundance and increases AR and CREB levels, leading to castration-resistant PCa (CRPC). Our findings revealed that STAT3 controls mTORC1 and CREB in metastatic disease, suggesting CREB as a promising target for lethal CRPC. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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