BACKGROUND: Prostate cancer ranks as the second most frequently diagnosed cancer in men worldwide. Recent research highlights the crucial roles IL6ST-mediated signaling pathways play in the development and progression of various cancers, particularly through hyperactivated STAT3 signaling. However, the molecular programs mediated by IL6ST/STAT3 in prostate cancer are poorly understood. METHODS: To investigate the role of IL6ST signaling, we constitutively activated IL6ST signaling in the prostate epithelium of a Pten-deficient prostate cancer mouse model in vivo and examined IL6ST expression in large cohorts of prostate cancer patients. We complemented these data with in-depth transcriptomic and multiplex histopathological analyses. RESULTS: Genetic cell-autonomous activation of the IL6ST receptor in prostate epithelial cells triggers active STAT3 signaling and significantly reduces tumor growth in vivo. Mechanistically, genetic activation of IL6ST signaling mediates senescence via the STAT3/ARF/p53 axis and recruitment of cytotoxic T-cells, ultimately impeding tumor progression. In prostate cancer patients, high IL6ST mRNA expression levels correlate with better recurrence-free survival, increased senescence signals and a transition from an immune-cold to an immune-hot tumor. CONCLUSIONS: Our findings demonstrate a context-dependent role of IL6ST/STAT3 in carcinogenesis and a tumor-suppressive function in prostate cancer development by inducing senescence and immune cell attraction. We challenge the prevailing concept of blocking IL6ST/STAT3 signaling as a functional prostate cancer treatment and instead propose cell-autonomous IL6ST activation as a novel therapeutic strategy.

• Keywords
• Cytotoxic T-cells, IL6ST/STAT3 signaling, Immune cell infiltration, L-gp130, Prostate cancer, Senescence, Senescence-associated secretory phenotype, Tumor microenvironment,
• MeSH
• Cyclin-Dependent Kinase Inhibitor p16 metabolism   genetics   MeSH
• Humans MeSH
• Disease Models, Animal MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Tumor Microenvironment * MeSH
• Tumor Suppressor Protein p53 * metabolism   genetics   MeSH
• Prostatic Neoplasms * pathology   metabolism   genetics   MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Signal Transduction * MeSH
• Cellular Senescence * MeSH
• STAT3 Transcription Factor * metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Cyclin-Dependent Kinase Inhibitor p16 MeSH
• Tumor Suppressor Protein p53 * MeSH
• STAT3 protein, human MeSH Browser
• STAT3 Transcription Factor * MeSH

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
• AMPK, AR, CREB, LKB1, Metformin, Prostate Cancer, STAT3, mTORC1,
• MeSH
• Diabetes Mellitus, Type 2 * MeSH
• Humans MeSH
• Neoplasm Recurrence, Local MeSH
• Metformin * pharmacology   MeSH
• Mechanistic Target of Rapamycin Complex 1 metabolism   MeSH
• Mice MeSH
• Prostatic Neoplasms * genetics   pathology   MeSH
• AMP-Activated Protein Kinases metabolism   MeSH
• STAT3 Transcription Factor genetics   metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Names of Substances
• Metformin * MeSH
• Mechanistic Target of Rapamycin Complex 1 MeSH
• AMP-Activated Protein Kinases MeSH
• STAT3 protein, human MeSH Browser
• Stat3 protein, mouse MeSH Browser
• Stk11 protein, mouse MeSH Browser
• STAT3 Transcription Factor MeSH