STAT3/LKB1 controls metastatic prostate cancer by regulating mTORC1/CREB pathway.
STAT3/LKB1 controls metastatic prostate cancer by regulating mTORC1/CREB pathway.
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DOI：
10.1186/s12943-023-01825-8
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发表时间：
2023-08-12
期刊：
影响因子：
37.3
通讯作者：
Kenner, Lukas
中科院分区：
文献类型：
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作者：
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;Greiner, Georg;D'Andrea, David;Ostman, Johnny R.;Tangermann, Simone;Hermanova, Ivana;Schaefer, 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
前列腺癌（PCa）是男性常见的致命癌症。转移性PCa（mPCa）是导致其致死性的主要因素，尽管其机制仍知之甚少。PTEN是mPCa中最常缺失的基因之一。在这里，我们显示了一个频繁的基因组共同缺失的PTEN和STAT 3在液体活检的mPCa患者。在Pten缺失小鼠前列腺模型中Stat 3的缺失导致LKB 1/pAMPK的减少，同时激活mTOR/CREB，导致转移性疾病。然而，Stat 3的组成性激活导致高LKB 1/pAMPK水平并抑制mTORC 1/CREB通路，从而阻止mPCa的发展。二甲双胍是最广泛的2型糖尿病治疗药物之一，它抑制肝脏中的mTORC 1，并需要LKB 1来介导葡萄糖稳态。我们发现二甲双胍治疗STAT 3/AR表达的PCa异种移植物导致肿瘤生长显著减少，伴随着mTORC 1/CREB、AR和PSA水平降低。缺失STAT 3/AR的PCa异种移植物几乎完全消除了二甲双胍介导的mTORC 1/CREB抑制。此外，二甲双胍治疗高Gleason分级和2型糖尿病的PCa患者导致检测不到mTORC 1水平和上调STAT 3表达。此外，CREB高表达的PCa患者的临床结局更差，PCa复发和转移复发的风险显著增加。总之，我们已经表明STAT 3通过LKB 1/pAMPK/mTORC 1/CREB信号传导控制mPCa，我们已经将其鉴定为治疗致死性mPCa的有希望的新型下游靶标。在线版本包含补充材料，可通过10.1186/s12943-023-01825-8获得。
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. The online version contains supplementary material available at 10.1186/s12943-023-01825-8.
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影响因子：
--
作者：
Roulhac PL;Ward JM;Thompson JW;Soderblom EJ;Silva M;Moseley MA 3rd;Jarvis ED
通讯作者：
Jarvis ED
将转录因子识别为单一的同源物2作为前列腺癌中潜在的生物标志物和免疫疗法靶标。
DOI：
10.1158/1078-0432.ccr-09-0911
发表时间：
2009-09-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Arredouani MS;Lu B;Bhasin M;Eljanne M;Yue W;Mosquera JM;Bubley GJ;Li V;Rubin MA;Libermann TA;Sanda MG
通讯作者：
Sanda MG
影响因子：
29
作者：
Howell JJ;Hellberg K;Turner M;Talbott G;Kolar MJ;Ross DS;Hoxhaj G;Saghatelian A;Shaw RJ;Manning BD
通讯作者：
Manning BD
影响因子：
64.5
作者：
Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
影响因子：
14.9
作者：
Colaprico A;Silva TC;Olsen C;Garofano L;Cava C;Garolini D;Sabedot TS;Malta TM;Pagnotta SM;Castiglioni I;Ceccarelli M;Bontempi G;Noushmehr H
通讯作者：
Noushmehr H