Urothelial Urinary Bladder Cancer Is Characterized by Stage-Dependent Aberrations in Metabolism of Bioactive Sphingolipids - stage-dependent aberrations and sphingolipid metabolism in urothelial cancer

Sep 21, 2026

Although dysregulated sphingolipid metabolism has been reported in many malignancies, bladder cancer has not been systematically examined in this context. This study analyzes bioactive sphingolipid metabolism across non-muscle-invasive and muscle-invasive urothelial urinary bladder cancer stages in 48 patients, comparing tumor tissue with healthy bladder samples. Sphingolipid content was quantified by HPLC, and transporter/enzyme mRNA levels by RT-PCR. SphK1, Spns2, and ABCC1 expression increased in UBC. Bioactive sphingolipid alterations were strongly stage-dependent, with muscle-invasive disease accumulating S1P and ceramide, while NMIBC did not differ from healthy tissue. Higher sphingosine and dihydroceramide were observed in MIBC, suggesting progression-linked S1P pathway dysregulation.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages8

Reading Time20 min

AccessFree to download

Abstract

Introduction

Sphingolipid metabolic pathways

Signaling roles in cancer

Materials and methods

Patient cohorts and tissue collection

HPLC and RT-PCR measurements

Results

Stage-independent transporter/enzyme expression changes

Stage-dependent sphingolipid accumulation

Discussion and conclusions

Communication Urothelial Urinary Bladder Cancer Is Characterized by Stage-Dependent Aberrations in Metabolism of Bioactive Sphingolipids Grzegorz Młynarczyk 1, Agnieszka Mikłosz 2, Adrian Chabowski 2 and Marcin Baranowski 2, * Citation: Młynarczyk, G.; Mikłosz, A.; Chabowski, A.; Baranowski, M. Urothelial Urinary Bladder Cancer Is Characterized by Stage-Dependent Aberrations in Metabolism of Bioactive Sphingolipids. Int. J. Mol. Sci. 2024, 25, 11889. [https://doi.org/](https://doi.org/)[ ](https://doi.org/)[10.3390/ijms252211889](10.3390/ijms252211889) 1 Department of Urology, Medical University of Białystok, Skłodowskiej-Curie 24A, 15-276 Białystok, Poland 2 Department of Physiology, Medical University of Bialystok, Mickiewicza 2c, 15-222 Białystok, Poland * [Correspondence: marcin.baranowski@umb.edu.pl](Correspondence: marcin.baranowski@umb.edu.pl); Tel.: +48-85-748-56-24; Fax: +48-85-748-55-86 Abstract: Although dysregulated sphingolipid metabolism was observed in many malignant tumors, bladder cancer has not yet been examined in this regard. This study aims to investigate the metabolism of bioactive sphingolipids across different stages of urothelial urinary bladder cancer (UBC). Forty-eight patients with UBC were included in this study. The neoplasms were classified as either non-muscle-invasive (NMIBC, n = 24) or muscle-invasive (MIBC, n = 24) . Samples of the healthy bladder tissue were taken from the patients who underwent radical cystectomy. The content of sphingolipids was measured using an HPLC method, and the mRNA expression of sphingolipid transporters and metabolizing enzymes was evaluated using RT-PCR. Compared to the healthy bladder tissue, the UBC, regardless of the stage, showed an elevated expression of SphK1, Spns2, and ABCC1 . The changes in the level of bioactive sphingolipids were strongly stage-dependent. MIBC showed accumulation of sphingosine-1-phosphate (S1P) and ceramide, whereas the content of thesesphingolipids in the NMIBC tumor was not different from that of healthy tissue. Moreover, MIBC, compared to NMIBC, was characterized by higher levels of sphingosine and dihydroceramide. We conclude that profound alterations in sphingolipid metabolism develop upon UBC transition from non-muscle-invasive to muscle-invasive. They include the accumulation of S1P, resulting from the increased availability of sphingosine generated from ceramide, which also builds up due to a further activation of its de novo synthesis. We hypothesize that the dysregulation of S1P metabolism leading to the accumulation of this tumor-promoting sphingolipid contributes to the progression of UBC. Keywords: dihydrosphingosine-1-phosphate; S1PL; sphinganine; sphingosine-1-phosphate lyase; sphingosine-1-phosphate phosphatase; TCC; transitional cell carcinoma 1. Introduction Academic Editor: Francesca Bersani Received: 1 October 2024 Revised: 1 November 2024 Accepted: 3 November 2024 Published: 5 November 2024 Copyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . Sphingolipids are not only vital components of cell membranes, but also act as bioactive molecules essential in signal transduction and the regulation of numerous cellular processes, such as proliferation, growth, migration, differentiation, and apoptosis [1] . Ceramide, which stands out as the central molecule in sphingolipid metabolism, is mainly synthesized through two pathways—the hydrolysis of sphingomyelin via the action ofsphingomyelinase and de novo synthesis. The de novo pathway begins with serine and palmitoyl-CoA condensation, catalyzed by serine palmitoyltransferase, producing 3-ketosphinganine, which is then rapidly converted to dihydr

FAQs

What was the main goal of the study?

To investigate how the metabolism of bioactive sphingolipids differs across stages of urothelial urinary bladder cancer.

How were patients and samples organized in this research?

Forty-eight patients were included, with tumors classified as non-muscle-invasive (NMIBC) or muscle-invasive (MIBC). Healthy bladder tissue samples were taken from patients undergoing radical cystectomy.

Which sphingolipid-related changes were most stage-dependent?

Muscle-invasive cancer showed accumulation of sphingosine-1-phosphate (S1P) and ceramide, while NMIBC levels were not different from healthy tissue; MIBC also had higher sphingosine and dihydroceramide.

Sep 21, 2026

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