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Die Rolle des Heparansulfatproteoglykans Syndecan-1 bei der Strahlenresistenz des Mammakarzinoms

Fachliche Zuordnung Gynäkologie und Geburtshilfe
Biochemie
Nuklearmedizin, Strahlentherapie, Strahlenbiologie
Förderung Förderung von 2020 bis 2024
Projektkennung Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 438042087
 
Erstellungsjahr 2024

Zusammenfassung der Projektergebnisse

Breast cancer (BrC) is the most common cancer in women. Radiation resistance represents a major challenge in BrC treatment. Membrane-bound heparan sulfate (HS) proteoglycans such as syndecan-1 (Sdc-1) contribute to tumorigenesis and tumor progression. We aimed to investigate the Sdc-1-dependent radiation response in triple negative breast cancer (TNBC) cells in mechanistic detail. For this purpose, Sdc-1 was downregulated using siRNA in five human TNBC cell lines. Both control and Sdc-1-KD cells were irradiated with the therapeutically relevant dose of 2 Gy for most of the experiments and with 2, 4, and 6 Gy for colony formation assays. Apoptosis, cell cycle progression, DNA repair, wound healing, collagen contraction, and spheroid formation were analyzed along with gene expression profiling and signal pathway analysis. To study their role in the radiotherapy response, HS chains were degraded in vitro in two TNBC cells using heparinases. Radioresistance was determined via colony formation assay. Cell cycle profile, stem cell characteristics, HS expression, beta integrin activation, and apoptosis were determined by flow cytometry. Additionally, cell motility was analyzed via wound-healing assays, and expression and activation of focal adhesion kinase (FAK), CDK-6, Src, and Erk1/2 were quantified by western blot pre- and post-irradiation. Finally, cytokine expression was analyzed by cytokine array. Radiation induced cell cycle changes, and DNA repair. Differential expression of CDK6, CDC20, CCNB1, AKRIC3, and PMS1, as well as changes in morphology and cytoskeletal protein levels were observed in irradiated Sdc1-KD cells. Altered FAK phosphorylation, lower CDK6 protein expression, and changes in sphere formation, collagen contraction, and wound healing were observed after Sdc1 KD and integrin β1 knockout (KO). Sdc1 and irradiation affected integrin recycling, and radiation was shown to be important for CDK6 expression and the maintenance of the cells in the G0 cell cycle phase. HS chain degradation induced apoptosis. While radiation promoted cell cycle changes, we observed increased radio-resistance and cell migration after HS degradation compared to controls that was even more prominent after irradiation. FAK was significantly activated in the heparinase-treated group. Additionally, Src was dysregulated in MDA-MB-231 cells. Secretion of GRO, CXCL1, IGFBP1, IL8, Angiogenin, and Osteoprotegerin was affected by HS degradation and radiotherapy. We conclude that Sdc-1 regulates the radioresistance of BrC cells in an integrin-FAK-CDK6-dependent manner. In addition, HS chains regulate radioresistance in TNBC. A mechanistic understanding of this process could provide the basis for targeting relevant signaling pathways to improve response to radiotherapy.

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