Prostate cancer (PCa) and Type 2 diabetes (T2D) often co-occur, yet their relationship remains elusive. While some studies suggest that T2D lowers PCa risk, others report conflicting data. This study investigates the effects of peroxisome proliferator-activated receptor (PPAR) agonists Bezafibrate, Tesaglitazar, and Pioglitazone on PCa tumorigenesis. Analysis of patient datasets revealed that high PPARG expression correlates with advanced PCa and poor survival. The PPARγ agonists Pioglitazone and Tesaglitazar notably reduced cell proliferation and PPARγ protein levels in primary and metastatic PCa-derived cells. Proteomic analysis identified intrinsic differences in mTORC1 and mitochondrial fatty acid oxidation (FAO) pathways between primary and metastatic PCa cells, which were further disrupted by Tesaglitazar and Pioglitazone. Moreover, metabolomics, Seahorse Assay-based metabolic profiling, and radiotracer uptake assays revealed that Pioglitazone shifted primary PCa cells' metabolism towards glycolysis and increased FAO in metastatic cells, reducing mitochondrial ATP production. Furthermore, Pioglitazone suppressed cell migration in primary and metastatic PCa cells and induced the epithelial marker E-Cadherin in primary PCa cells. In vivo, Pioglitazone reduced tumor growth in a metastatic PC3 xenograft model, increased phosho AMPKα and decreased phospho mTOR levels. In addition, diabetic PCa patients treated with PPAR agonists post-radical prostatectomy implied no biochemical recurrence over five to ten years compared to non-diabetic PCa patients. Our findings suggest that Pioglitazone reduces PCa cell proliferation and induces metabolic and epithelial changes, highlighting the potential of repurposing metabolic drugs for PCa therapy.

Center for Biomarker Research in Medicine GmbH Graz Austria

Center for Cancer Research Medical University of Vienna Vienna Austria

Center of Physiology and Pharmacology Department of Vascular Biology and Thrombosis Research Medical University of Vienna Vienna Austria

Central European Institute of Technology Masaryk University Brno 62500 Czech Republic

Christian Doppler Laboratory for Applied Metabolomics Medical University of Vienna Vienna Austria

Department of Biological Sciences and Pathobiology Unit of Physiology and Biophysics University of Veterinary Medicine Vienna Austria

Department of Biomedical Imaging and Image Guided Therapy Division of Nuclear Medicine Medical University of Vienna Vienna Austria

Department of Molecular Biology Umeå University Umea Sweden

Department of Molecular Sciences Swedish University of Agricultural Sciences 75007 Uppsala Sweden

Department of Nutritional Science University of Vienna Vienna Austria

Department of Pathology Medical University of Vienna Vienna Austria

Department of Urology Medical University of Innsbruck Innsbruck Austria

Division of Cellular and Molecular Pathology Department of Pathology University of Cambridge Cambridge UK

Faculty of Medicine Masaryk University Brno Czech Republic

Institute for Genetics Cologne Excellence Cluster of Cellular Stress Responses in Aging Associated Diseases Cologne Germany

Unit of Laboratory Animal Pathology Institute of Pathology University of Veterinary Medicine Vienna Vienna Austria

University of Vienna Vienna Austria

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