PARP14-mediated glycolysis enhances Tamoxifen resistance in estrogen receptor + breast cancer cells.

BACKGROUND: Resistance to Tamoxifen is a major challenge in the therapeutic management of estrogen receptor (ER) + breast cancer (BC). Glycolysis, as reported, exerts a crucial influence on the regulation of Tamoxifen resistance in BC, highlighting the need for further investigation into the mechanisms by which it contributes to Tamoxifen resistance in ER + BC. METHOD: Bioinformatics was employed to analyze the differential expression of PARP14 between Tamoxifen-responsive and -resistant ER + BC tissues. Poly (ADP-ribose) polymerase family member 14 (PARP14) expression in Tamoxifen-resistant cell lines (T47D/TAMR) was quantified through quantitative real time polymerase chain reaction (qRT-PCR). A subsequent Gene Set Enrichment Analysis (GSEA) was conducted to determine the relationship between PARP14 and glycolysis-related genes. The assessment of glycolytic activity included measurements of hexokinase II (HK2) expression, extracellular acidification rate (ECAR), oxygen consumption rate (OCR), glucose uptake, lactate secretion, and adenosine Triphosphate (ATP) synthesis. Cellular proliferation was evaluated using a colony formation assay, cell viability was assessed with the Cell Counting Kit-8 (CCK-8) assay to establish the half maximal inhibitory concentration (IC(50)) value, and apoptosis was measured by flow cytometry. RESULTS: PARP14 exhibited elevated expression in Tamoxifen-resistant tissues and cells such as T47D/TAMR, where its knockdown increased responsiveness to Tamoxifen. PARP14 was also notably associated with the glycolysis pathway, showing a positive correlation with genes that enhance glycolysis, and its suppression led to decreased glycolysis in T47D/TAMR cells. Overexpression of PARP14 in vitro induced Tamoxifen resistance in these cells, but co-administration of the glycolytic inhibitor 2-DG could recover their sensitivity to Tamoxifen. CONCLUSION: PARP14 facilitates Tamoxifen resistance in ER + BC cells via the activation of the glycolysis pathway. We suspect that targeting PARP14 or the glycolytic pathway could be a viable therapeutic option for ER + BC that has developed resistance to Tamoxifen.