Dataset Information

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

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.

SUBMITTER: Pencik J

PROVIDER: S-EPMC10422794 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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

Pencik Jan J Philippe Cecile C Schlederer Michaela M Atas Emine E Pecoraro Matteo M Grund-Gröschke Sandra S Li Wen Jess WJ Tracz Amanda A Heidegger Isabel I Lagger Sabine S Trachtová Karolína K Oberhuber Monika M Heitzer Ellen E Aksoy Osman O Neubauer Heidi A HA Wingelhofer Bettina B Orlova Anna A Witzeneder Nadine N Dillinger Thomas T Redl Elisa E Greiner Georg G D'Andrea David D Östman Johnny R JR Tangermann Simone S Hermanova Ivana I Schäfer Georg G Sternberg Felix F Pohl Elena E EE Sternberg Christina C Varady Adam A Horvath Jaqueline J Stoiber Dagmar D Malcolm Tim I TI Turner Suzanne D SD Parkes Eileen E EE Hantusch Brigitte B Egger Gerda G Rose-John Stefan S Poli Valeria V Jain Suneil S Armstrong Chris W D CWD Hoermann Gregor G Goffin Vincent V Aberger Fritz F Moriggl Richard R Carracedo Arkaitz A McKinney Cathal C Kennedy Richard D RD Klocker Helmut H Speicher Michael R MR Tang Dean G DG Moazzami Ali A AA Heery David M DM Hacker Marcus M Kenner Lukas L

Molecular cancer 20230812 1

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 metastati ...[more]

PMID: 37573301

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Project description:BackgroundThe study of the immune microenvironment in prostate cancer (PRAD) has brought new opportunities for the current traditional treatment regimens. Therefore, our goal is to develop a universal immunodiagnostic marker to improve patient survival.MethodsBioinformatics analysis: We collected 591 samples from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) cohorts and evaluated the abundance and distribution of immune cell members in the PRAD expression profile matrix in the mixed cell population by CIBERSORT, ESTIMATE, single-sample gene set enrichment analysis (ssGSEA), and other methods. The target genes related to PRAD immune microenvironment and tumor mutation load were obtained by overlap analysis and verified by pan-cancer analysis. Cell experiment: The cell transfection scheme was designed, and the experiment was divided into three groups: overexpressing lactoferrin (LTF) group, empty plasmid group, and control group. After obtaining cells in each group, the gene and protein expression levels of LTF and signal transduction of signal transducer and activator of transcription 3 (STAT3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in the above three groups were detected by real-time PCR and Western blot, respectively. Finally, the level of GM-CSF secretion in the three groups was detected by ELISA.ResultsMacrophages, resting mast cells, and plasma cells play an important role in PRAD immune microenvironment. In addition, high tumor mutation load [tumor mutational burden (TMB)] was positively correlated with lymph node metastasis in patients with PRAD. As the core gene of the PRAD immune microenvironment, the low expression of LTF in PRAD promotes the occurrence of immunodeficiency, PRAD, and the enrichment of the Janus kinase (JAK)/STAT3 signal pathway. Through cell experiments, it was found that the content of LTF mRNA and protein increased significantly, while the content of STAT3 and GM-CSF mRNA and protein decreased significantly in the overexpressed LTF group. The level of GM-CSF in the supernatant of cell culture was significantly decreased in the overexpression group of LTF.ConclusionThe core gene we proposed is one of the most promising biomarkers to improve the overall survival rate of PRAD and provides an important theoretical basis for the study of the mechanism of the LTF-mediated JAK/STAT3 pathway in PRAD.

Dataset Information

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

Publications

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

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