STAT3/LKB1 controls metastatic prostate cancer by regulating mTORC1/CREB pathway.
- Autor(en)
- J Pencik, C Philippe, M Schlederer, E Atas, M Pecoraro, S Grund-Gröschke, WJ Li, A Tracz, I Heidegger, S Lagger, K Trachtová, M Oberhuber, E Heitzer, O Aksoy, HA Neubauer, B Wingelhofer, A Orlova, N Witzeneder, T Dillinger, E Redl, G Greiner, D D'Andrea, JR Östman, S Tangermann, I Hermanova, G Schäfer, F Sternberg, EE Pohl, C Sternberg, A Varady, J Horvath, D Stoiber, TI Malcolm, SD Turner, EE Parkes, B Hantusch, G Egger, S Rose-John, V Poli, S Jain, CWD Armstrong, G Hoermann, V Goffin, Fritz Aberger, R Moriggl, A Carracedo, C McKinney, RD Kennedy, H Klocker, MR Speicher, DG Tang
- 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.
- Organisation(en)
- Institut für Anorganische Chemie, Department für Pharmazeutische Wissenschaften, Department für Biochemie und Zellbiologie, HR Services, Institut für Bildungswissenschaft, Department für Ernährungswissenschaften, Institut für Osteuropäische Geschichte, Communication Networks & Infrastructure, Institut für Mathematik, Department für Mikrobiologie, Immunbiologie und Genetik, Institut für Theater-, Film- und Medienwissenschaft
- Journal
- Molecular Cancer
- ISSN
- 1476-4598
- DOI
- https://doi.org/10.1186/s12943-023-01825-8
- Publikationsdatum
- 08-2023
- Peer-reviewed
- Ja
- ÖFOS 2012
- 106023 Molekularbiologie
- Sustainable Development Goals
- SDG 3 – Gesundheit und Wohlergehen
- Link zum Portal
- https://ucrisportal.univie.ac.at/de/publications/90ae9950-0d10-49d9-be0c-0d1cd5f63c8e