SDC4 silencing promotes cell cycle arrest at the restriction point (R point) in anoikis-resistant endothelial cells

TL;DR

Silencing SDC4 in resistant endothelial cells stops the cell cycle and increases sensitivity to cell death, suggesting it could be a target for cancer treatment.

Contribution

This study reveals SDC4's role in cell cycle regulation in anoikis-resistant cells and its potential as a cancer therapeutic target.

Findings

SDC4 silencing increases p27 expression and impairs cyclin E-CDK2 activity, hindering cell cycle progression.

SDC4 silencing reduces cyclin B1 and lowers IBR indices for cyclins and CDKs, indicating reduced cell cycle activity.

SDC4 silencing increases susceptibility to anoikis in resistant endothelial cells.

Abstract

Many tumor cells exhibit resistance to anoikis, facilitating their invasion and contributing to tumor metastasis. Previous studies have shown that anoikis-resistant endothelial cells overexpress syndecan-4 (SDC4), a co-receptor for growth factors that interacts with extracellular matrix (ECM) proteins. While SDC4 is well-known for its role in cellular processes such as adhesion, migration, and proliferation, its specific involvement in cell cycle dysregulation in tumor cells remains poorly understood. This study aimed to investigate the role of SDC4 in regulating the cell cycle in anoikis-resistant endothelial cells. Methods included the use of wild-type endothelial cells (EC), EJ-ras oncogene-transfected EC (EJ-ras EC), anoikis-resistant EC (Adh1-EC), and SDC4-silenced EC (miR-Syn-4-1-Adh-EC). Gene and protein expression of regulatory molecules across different phases of the cell cycle were analyzed using qPCR, western blotting, and flow cytometry. The Integrated Biomarker Response (IBR) index was employed to interpret cellular responses, and cell viability was assessed after adhesion blockade. Results showed that while cyclin D1 was highly expressed in the G1 phase, SDC4-silenced cells exhibited increased p27 expression, which impairs the activity of the cyclin E-CDK2 complex, suggesting a potential hindrance to cell cycle progression. Additionally, a reduction in cyclin B1 expression was observed. The IBR index for cyclins and CDKs was 2.19 and 3.24, respectively, following SDC4 silencing, compared to 4.72 and 4.41 in anoikis-resistant cells. Furthermore, SDC4 silencing increased the cells’ susceptibility to anoikis. These findings highlight SDC4’s ability to modulate key processes involved in cancer development, emphasizing its potential as a therapeutic target in cancer treatment.

The online version contains supplementary material available at 10.1007/s10616-026-00931-x.

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