STAT3/LKB1 通过调控 mTORC1/CREB 途径控制转移性前列腺癌。
STAT3/LKB1 controls metastatic prostate cancer by regulating mTORC1/CREB pathway.
发表日期：2023 Aug 12
作者：
Jan Pencik, Cecile Philippe, Michaela Schlederer, Emine Atas, 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, Felix Sternberg, Elena E Pohl, Christina Sternberg, Adam Varady, Jaqueline Horvath, Dagmar Stoiber, Tim I Malcolm, Suzanne D Turner, Eileen E 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, Ali A Moazzami, David M Heery, Marcus Hacker, Lukas Kenner
来源：
BIOMEDICINE & PHARMACOTHERAPY
摘要：
前列腺癌（PCa）是男性常见且致命的一种癌症。转移性前列腺癌（mPCa）是其致死性的主要因素，尽管其机制尚不明确。PTEN是mPCa中最常见的基因之一。在此，我们展示了在mPCa患者的液体活检中PTEN和STAT3的基因组共删除现象。在Pten敲除小鼠前列腺模型中，Stat3的丧失导致LKB1/pAMPK的减少，并同时激活mTOR/CREB，从而导致转移性疾病。然而，Stat3的持续激活导致高水平的LKB1/pAMPK并抑制mTORC1/CREB通路，防止mPCa的发展。二甲双胍是治疗2型糖尿病最常用的药物之一，在肝脏中抑制mTORC1并需要LKB1介导葡萄糖稳态。我们发现，二甲双胍治疗STAT3/AR表达的前列腺癌异种移植瘤可显著抑制肿瘤生长，并伴随mTORC1/CREB、AR和PSA水平的下降。删除STAT3/AR的前列腺癌异种移植瘤几乎完全抑制了二甲双胍对mTORC1/CREB的抑制作用。此外，高Gleason分级和2型糖尿病的前列腺癌患者经二甲双胍治疗后，mTORC1的水平下降，而STAT3的表达上调。此外，具有高CREB表达的前列腺癌患者具有更糟糕的临床结果，并且明显增加了前列腺癌复发和转移复发的风险。总之，我们已经表明STAT3通过LKB1/pAMPK/mTORC1/CREB信号通路控制mPCa，我们认为这是治疗致命性mPCa的有前途的新靶点。© 2023. BioMed Central Ltd., Springer Nature的一部分。
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.© 2023. BioMed Central Ltd., part of Springer Nature.