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Selected Publication:
SHR Neuro Cancer Cardio Lipid Metab Microb
Pencik, J; Philippe, C; Schlederer, M; Atas, E; Pecoraro, M; Grund-Gröchke, S; Li, W; Tracz, A; Heidegger, I; Lagger, S; Trachtová, K; Oberhuber, M; Heitzer, E; Aksoy, O; Neubauer, HA; Wingelhofer, B; Orlova, A; Witzeneder, N; Dillinger, T; Redl, E; Greiner, G; D'Andrea, D; Östman, JR; Tangermann, S; Hermanova, I; Schäfer, G; Sternberg, F; Pohl, EE; Sternberg, C; Varady, A; Horvath, J; Stoiber, D; Malcolm, TI; Turner, SD; Parkes, EE; Hantusch, B; Egger, G; Rose-John, S; Poli, V; Jain, S; Armstrong, CWD; Hoermann, G; Goffin, V; Aberger, F; Moriggl, R; Carracedo, A; McKinney, C; Kennedy, RD; Klocker, H; Speicher, MR; Tang, DG; Moazzami, AA; Heery, DM; Hacker, M; Kenner, L.
STAT3/LKB1 controls metastatic prostate cancer by regulating mTORC1/CREB pathway
MOL CANCER. 2023; 22(1): 133
Doi: 10.1186/s12943-023-01825-8
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- Leading authors Med Uni Graz
- Kenner Lukas
- Co-authors Med Uni Graz
- Heitzer Ellen
- Speicher Michael
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- Abstract:
- 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.
- Find related publications in this database (Keywords)
- STAT3
- mTORC1
- AR
- Prostate Cancer
- LKB1
- AMPK
- CREB
- Metformin