Moazzami, Ali
- Department of Molecular Sciences, Swedish University of Agricultural Sciences
Abstract
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 gamma agonists Pioglitazone and Tesaglitazar notably reduced cell proliferation and PPAR gamma 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 alpha 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
Metabolic rewiring; Type 2 diabetes mellitus (T2DM); PPAR agonists; Cancer therapy; Oxygen consumption rate; Extracellular acidification; Energy metabolism
Published in
Molecular Cancer
2025, volume: 24, number: 1, article number: 134
Publisher: BMC
SLU Authors
UKÄ Subject classification
Cell and Molecular Biology
Cancer and Oncology
Publication identifier
- DOI: https://doi.org/10.1186/s12943-025-02320-y
Permanent link to this page (URI)
https://res.slu.se/id/publ/141879