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Updated: Mar 28, 2026
Assessment of Mitochondrial Functions and Cell Viability in Renal Cells Overexpressing Protein Kinase C Isozymes
Published on: January 7, 2013
Intracellular prostaglandin E2 mediates cisplatin-induced proximal tubular cell death
Ana B Fernández-Martínez1, Selma Benito Martínez2, Francisco J Lucio Cazaña2
1Departamento de Biología, Universidad Autónoma de Madrid, Madrid, Spain.
Abstract:
Nephrotoxicity, particularly in the proximal tubule, limits the therapeutic efficacy of the antineoplastic drug cisplatin. The signaling mechanisms appear to be multifactorial, involving inflammation, oxidative stress, and caspase. Here we studied the role of intracellular prostaglandin E2 (iPGE2) in cisplatin's cytotoxicity in human proximal tubular HK-2 cells. Cisplatin-induced apoptotic cell death was prevented by inhibitors of the prostaglandin transporter (PGT) or by PGT knock-down or by pharmacologic inhibition of PGE2 EP receptors or cyclo-oxygenase-2 (COX-2). iPGE2 also increased in cisplatin-treated cells, which was probably due to increased expression of COX-2, microsomal PGE2 synthase-1 and PGT, and was prevented by inhibitors of PGT or COX-2. Thus iPGE2, most likely acting through intracellular EP receptors, mediates cisplatin-induced HK-2 cell death. Importantly, the tumoricidal effect of cisplatin on human cervical adenocarcinoma HeLa cells was not affected by a pharmacologic inhibitor of PGT. In conclusion, iPGE2 may play a significant role in the pathogenesis of cisplatin’s nephrotoxicity and treatment with PGT inhibitors might represent a novel strategy in its prevention.
Insights
Intracellular prostaglandin E2 (iPGE2) drives cisplatin-induced kidney cell death. Inhibiting the prostaglandin transporter (PGT) or cyclo-oxygenase-2 (COX-2) protected kidney cells, suggesting a new strategy to prevent cisplatin nephrotoxicity.
Area of Science:
- Nephrology
- Molecular Pharmacology
- Oncology
Background:
- Cisplatin is an effective antineoplastic drug, but its use is limited by nephrotoxicity, particularly affecting proximal tubule cells.
- The mechanisms underlying cisplatin-induced nephrotoxicity are complex, involving inflammation, oxidative stress, and apoptosis.
- Intracellular prostaglandin E2 (iPGE2) has emerged as a potential mediator in cellular injury.
Purpose of the Study:
- To investigate the role of intracellular prostaglandin E2 (iPGE2) in cisplatin-induced cytotoxicity in human proximal tubular HK-2 cells.
- To explore the potential of targeting prostaglandin transporter (PGT) or cyclo-oxygenase-2 (COX-2) pathways for preventing cisplatin nephrotoxicity.
Main Methods:
- HK-2 cells were treated with cisplatin, and the effects of PGT inhibitors, PGT knock-down, EP receptor antagonists, and COX-2 inhibitors were assessed.
- Levels of iPGE2, COX-2, microsomal PGE2 synthase-1, and PGT were measured in cisplatin-treated cells.
- The impact of PGT inhibition on cisplatin's tumoricidal effect on HeLa cells was evaluated.
Main Results:
- Cisplatin-induced apoptotic cell death in HK-2 cells was significantly reduced by inhibiting PGT, EP receptors, or COX-2.
- Cisplatin treatment led to increased iPGE2 levels, associated with elevated expression of COX-2, microsomal PGE2 synthase-1, and PGT.
- Inhibition of PGT did not affect the tumoricidal activity of cisplatin against HeLa cells.
Conclusions:
- Intracellular PGE2, likely acting via intracellular EP receptors, mediates cisplatin-induced cytotoxicity in proximal tubular cells.
- Targeting the PGT pathway may offer a novel therapeutic strategy to prevent cisplatin nephrotoxicity without compromising its anti-cancer efficacy.
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