2. Academic Validation
  3. Targeting carbonic anhydrase IX/XII prevents the anti-ferroptotic effect of stromal lactic acid in prostate carcinoma

Targeting carbonic anhydrase IX/XII prevents the anti-ferroptotic effect of stromal lactic acid in prostate carcinoma

  • Mol Oncol. 2025 Jun 26. doi: 10.1002/1878-0261.70083.
Elisa Pardella 1,  Giuseppina Comito 1,  Luigi Ippolito 1,  Erica Pranzini 1,  Marta Iozzo 1,  Giulia Gangarossa 1,  Francesca Virgilio 1,  Silvia Bua 2,  Alessio Nocentini 2,  Giada Sandrini 3,  Nicla Lorito 1,  Marina Bacci 1,  Gabriella Nesi 4,  Pietro Spatafora 5 6,  Sergio Serni 5 6,  Claudiu T Supuran 2,  Andrea Morandi 1,  Paola Chiarugi 1,  Elisa Giannoni 1
Affiliations

Affiliations

  • 1 Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Italy.
  • 2 Department of NEUROFARBA, Pharmaceutical and Nutraceutical Section, University of Florence, Italy.
  • 3 Institute of Oncology Research (IOR), Università della Svizzera Italiana (USI), Bellinzona, Switzerland.
  • 4 Section of Pathological Anatomy, Department of Health Sciences, University of Florence, Italy.
  • 5 Unit of Urological Robotic Surgery and Renal Transplantation, Careggi Hospital, University of Florence, Italy.
  • 6 Department of Experimental and Clinical Medicine, University of Florence, Italy.
PMID: 40569831 DOI: 10.1002/1878-0261.70083
Abstract

Ferroptosis is a form of regulated cell death dependent on iron-driven phospholipid peroxidation and is controlled by both cell autonomous and non-cell autonomous mechanisms. In prostate Cancer (PCa), tumor cells engage in a metabolic crosstalk with cancer-associated fibroblasts (CAFs), resulting in increased utilization of CAF-secreted lactic acid, that ultimately supports Cancer aggressiveness. In this context, the effect of the prostate tumor microenvironment in modulating Ferroptosis sensitivity has not yet been extensively investigated. Here, we demonstrate that CAF-secreted lactic acid protects PCa cells from Ferroptosis induction and supports the upregulation of the antioxidant enzyme Glutathione Peroxidase 4 (GPX4). Interestingly, targeting Carbonic Anhydrase IX/XII (CA IX/XII), the main regulators of microenvironmental acidosis, in tumor and stromal compartments hinders lactic acid shuttle within the tumor-stroma interplay and thus, prevents Ferroptosis resistance induced by lactic acid. Analyses of tissue samples from PCa patients also revealed that GPX4, CA IX, and CA XII expression levels increase during PCa progression. Overall, these findings support a role for stromal lactic acid in mediating Ferroptosis resistance in PCa, identifying CA IX/XII as potential therapeutic targets regulating Ferroptosis sensitivity.

Keywords

cancer‐associated fibroblasts; carbonic anhydrase; ferroptosis; lactic acid; prostate cancer; tumor microenvironment.

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