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

Pencik, Jan; Philippe, Cecile; Schlederer, Michaela; Atas, Emine; Pecoraro, Matteo; Grund-Gröschke, Sandra; Li, Wen (Jess); Tracz, Amanda; Heidegger, Isabel; Lagger, Sabine; Trachtová, Karolína; Oberhuber, Monika; Heitzer, Ellen; Aksoy, Osman; Neubauer, Heidi A.; Wingelhofer, Bettina; Orlova, Anna; Witzeneder, Nadine; Dillinger, Thomas; Redl, Elisa; Greiner, Georg; D’Andrea, David; Östman, Johnny R.; Tangermann, Simone; Hermanova, Ivana; Schäfer, Georg; Sternberg, Felix; Pohl, Elena E.; Sternberg, Christina; Varady, Adam; Horvath, Jaqueline; Stoiber, Dagmar; Malcolm, Tim I.; Turner, Suzanne D.; Parkes, Eileen E.; Hantusch, Brigitte; Egger, Gerda; Rose-John, Stefan; Poli, Valeria; Jain, Suneil; Armstrong, Chris W.D.; Hoermann, Gregor; Goffin, Vincent; Aberger, Fritz; Moriggl, Richard; Carracedo, Arkaitz; McKinney, Cathal; Kennedy, Richard D.; Klocker, Helmut; Speicher, Michael R.; Tang, Dean G.; Moazzami, Ali A.; Heery, David M.; Hacker, Marcus; Kenner, Lukas

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.

• Journal Article Type: Article
• Acceptance Date: Jul 14, 2023
• Online Publication Date: Aug 12, 2023
• Publication Date: 2023
• Deposit Date: Aug 21, 2023
• Publicly Available Date: Aug 31, 2023
• Journal: Molecular Cancer
• Electronic ISSN: 1476-4598
• Publisher: Springer Science and Business Media LLC
• Peer Reviewed: Peer Reviewed
• Volume: 22
• Article Number: 133
• DOI: https://doi.org/10.1186/s12943-023-01825-8
• Keywords: AMPK, STAT3, AR, Prostate Cancer, LKB1, Metformin, mTORC1, CREB
• Public URL: https://nottingham-repository.worktribe.com/output/24414717
• Additional Information: Received: 23 March 2023; Accepted: 14 July 2023; First Online: 12 August 2023; : ; : Animal experiments were reviewed and approved by the Austrian ministry authorities and conducted according to relevant regulatory standards (BMWFW-66.009/0281-I/3b/2012 and BMWFW-66.009/0088-WF/V/3b/2018).The clinical studies were approved by the Ethical Committee of the Medical University Innsbruck (study number AN2014-0145 336/4.24) by the Ethical Committee of the Medical University of Graz (approval number 21–228 ex 09/10), conducted according to the Declaration of Helsinki, and written informed consent to participate in research studies was obtained from all patients.; : The authors declare no competing interests.