The anti-diabetic PPARy agonist Pioglitazone inhibits cell proliferation and induces metabolic reprogramming in prostate cancer

Emine Atas; Kerstin Berchtold; Michaela Schlederer; Sophie Prodinger; Felix Sternberg; Perla Pucci; Christopher Steel; Jamie D. Matthews; Emily R. James; Cécile Philippe; Karolína Trachtová; Ali A. Moazzami; Nastasiia Artamonova; Felix Melchior; Torben Redmer; Gerald Timelthaler; Elena E. Pohl; Suzanne D. Turner; Isabel Heidegger; Marcus Krueger; Ulrike Resch; Lukas Kenner

doi:10.1186/s12943-025-02320-y

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Title (eng)

The anti-diabetic PPARy agonist Pioglitazone inhibits cell proliferation and induces metabolic reprogramming in prostate cancer

Author

Emine Atas

Kerstin Berchtold

Michaela Schlederer

Sophie Prodinger

Felix Sternberg

University of Veterinary Medicine Vienna

Perla Pucci

Christopher Steel

Jamie D. Matthews

Emily R. James

Cécile Philippe

Karolína Trachtová

Ali A. Moazzami

Nastasiia Artamonova

Felix Melchior

Torben Redmer

University of Veterinary Medicine Vienna

Gerald Timelthaler

Elena E. Pohl

Suzanne D. Turner

Isabel Heidegger

Marcus Krueger

Ulrike Resch

Lukas Kenner

University of Veterinary Medicine Vienna

Abstract (eng)

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 PPAR? agonists Pioglitazone and Tesaglitazar notably reduced cell proliferation and PPAR? 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 AMPK? 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.

Keywords (eng)

Set Enrichment AnalysisMass-SpectrometryExpressionEfficacyPlatformOutcomesHealthMen

Type (eng)

journal article

Language

[eng]

Persistent identifier

https://phaidra.vetmeduni.ac.at/o:4140

DOI

10.1186/s12943-025-02320-y

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Title (eng)