Sulfatide Acts as a Regulatory Molecule Controlling β1 Integrin - STAT5 Signaling and BOLA2-Dependent Apoptotic Pathway in Breast Cancer Cells

Sep 23, 2026

Cell membrane glycosylations regulate signaling, adhesion, and immune recognition, and abnormal glycosylation is a cancer hallmark that supports progression. Sulfatide (SM4), a glycosphingolipid produced by galactosylceramide sulfotransferase (CST), links altered metabolism to apoptosis and gene regulation. In breast cancer cells, CST/SM4 overproduction downregulates BOLA2 and increases apoptotic sensitivity, with BOLA2 overexpression protecting against doxorubicin-induced apoptosis.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages17

Reading Time43 min

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Introduction

Cell membrane glycosylation and cancer

Sulfatide and sulfolipids in tumors

Prior findings in breast cancer

Article Sulfatide Acts as a Regulatory Molecule Controlling β1 Integrin–STAT5 Signaling and BOLA2-Dependent Apoptotic Pathway in Breast Cancer Cells Jaroslaw Suchanski *, Weronika Woldanska, Adam Sciana, Barbara Suchanska and Leszek Moniakowski Academic Editors: Erik A.C. Wiemer and Anna Perri Received: 29 October 2025 Revised: 2 December 2025 Accepted: 6 December 2025 Published: 9 December 2025 Citation: Suchanski, J.; Woldanska, W.; Sciana, A.; Suchanska, B.; Moniakowski, L. Sulfatide Acts as a Regulatory Molecule Controlling β1 Integrin–STAT5 Signaling and BOLA2-Dependent Apoptotic Pathway in Breast Cancer Cells. Int. J. Mol. Sci. 2025, 26, 11873. [https://](https://)[ ](https://)[doi.org/10.3390/ijms262411873](doi.org/10.3390/ijms262411873) [Copyright:](Copyright:) © 2025 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://creativecommons.org/](https://creativecommons.org/)[ ](https://creativecommons.org/)[licenses/by/4.0/](licenses/by/4.0/)) . Department of Biochemistry and Molecular Biology, Wroclaw University of Environmental and Life Sciences, C.K. Norwida 31, 50-375 Wroclaw, Poland * [Correspondence: jaroslaw.suchanski@upwr.edu.pl](Correspondence: jaroslaw.suchanski@upwr.edu.pl) Abstract Cell membrane glycosylations play a critical role in regulating cell signaling, adhesion, and immune recognition. Abnormal glycosylation is a hallmark of cancer and promotes tumor progression. Sulfatide (SM4), a glycosphingolipid synthesized by galactosylceramide sulfotransferase (CST), is frequently altered in cancers, including breast cancer. Our previous studies identified SM4 as an adhesive molecule that enhances metastasis through interactions with platelets and endothelium; however, its elevated levels increase apoptotic sensitivity and reduce tumorigenicity. Here, we elucidate the molecular mechanisms linking sulfatide metabolism to apoptosis and gene regulation. Using MDA-MB-231 and MDA-MB-468 breast cancer cells with altered CST/SM4 levels, RNA sequencing and functional analyses revealed that overproduction of the CST/SM4 significantly downregulated BOLA2, a gene in the CIAPIN1 pathway involved in apoptosis. RT-qPCR and Western blot confirmed an inverse relationship between CST/SM4 and BOLA2 . Overexpressing BOLA2 provided resistance to doxorubicin-induced apoptosis, suggesting that SM4-mediated repression of BOLA2 increases apoptotic sensitivity. Luciferase assays showed reduced BOLA2 promoter activity in SM4-enriched cells. Transcription factor profiling and Electrophoretic Mobility Shift Assay demonstrated that SM4 suppresses STAT5 activation, which directly binds and regulates the BOLA2 promoter. SM4 also altered integrin profiles by upregulating β4/β5 and downregulating β1 subunits. Reintroducing β1 integrin restored STAT5 activation and BOLA2 expression, positioning β1 integrin upstream of STAT5 . Collectively, these findings identify a novel sulfatide-dependent β1 integrin–STAT5– BOLA2 pathway controlling apoptosis in breast cancer cells. SM4 suppresses β1 integrin and STAT5-mediated BOLA2 transcription, promoting apoptosis, while β4/β5 upregulation may facilitate invasion. This pathway represents a potential therapeutic target in breast cancer. Keywords: sulfatide; galactosylceramide sulfotransferase; BOLA2; STAT5; β1 integrin; apoptosis; invasion; breast cancer 1. Introduction The uniqueness of cell membranes is characterized by the presence of carbohydrate chains carried by glycoconjugates—glycoproteins, proteoglycans, and glycosphingolipids (GSLs)—which are essential for maintaining cellular membrane structure and function [1] . This multitude and diversity in glycosylation patterns are not merely biological variations, but are critical for the precise regulation of cellular processes, underpinning essential functions such as signaling,

FAQs

What is the main regulatory pathway described for breast cancer cells?

The study identifies a sulfatide-dependent β1 integrin - STAT5 - BOLA2 pathway that controls apoptotic sensitivity in breast cancer cells.

How does CST/SM4 affect BOLA2 and apoptosis?

Overproduction of CST/SM4 significantly downregulates BOLA2, and this repression increases sensitivity to apoptosis, including doxorubicin-induced apoptosis.

What experimental evidence supports STAT5 involvement in BOLA2 regulation?

Transcription factor profiling and electrophoretic mobility shift assay show that SM4 suppresses STAT5 activation, and STAT5 directly binds the BOLA2 promoter.

Sep 23, 2026

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