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Research article2023Peer reviewedOpen access

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

Pencik, Jan; Philippe, Cecile; Schlederer, Michaela; Atas, Emine; Pecoraro, Matteo; Grund-Groeschke, Sandra; Li, Wen (Jess); Tracz, Amanda; Heidegger, Isabel; Lagger, Sabine; Trachtova, Karolina; Oberhuber, Monika; Heitzer, Ellen; Aksoy, Osman; Neubauer, Heidi A.; Wingelhofer, Bettina; Orlova, Anna; Witzeneder, Nadine; Dillinger, Thomas; Redl, Elisa;
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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.

Keywords

STAT3; mTORC1; AR; Prostate Cancer; LKB1; AMPK; CREB; Metformin

Published in

Molecular Cancer
2023, Volume: 22, number: 1, article number: 133
Publisher: BMC

      SLU Authors

      • Sustainable Development Goals

      Ensure healthy lives and promote well-being for all at all ages

      UKÄ Subject classification

      Cancer and Oncology

      Publication identifier

      DOI: https://doi.org/10.1186/s12943-023-01825-8

      Permanent link to this page (URI)

      https://res.slu.se/id/publ/126518