Co-treatment with melatonin and ortho-topolin riboside exhibits anti-proliferation activity in radioresistant MDA-MB-231 cells by altering metabolic and transcriptomic profiles

Abstract

Radiation therapy represents the primary treatment option for triple-negative breast cancer. However, radio resistance is associated with a poor prognosis and an increased risk of recurrence. Radioresistant MDA-MB-231 cells, a radioresistant triple-negative breast cancer cell line, were co-treated with ortho-topolin riboside and melatonin. The energy metabolism, metabolic profile, and transcriptomic profile of these cells were studied using XFe, gas chromatography, and next-generation sequencing. The combination treatment simultaneously inhibited glycolysis and mitochondrial respiration and inhibited the glycolytic transport chain by decreasing ATP5MC1 and ATP5ME1 gene expression, which synthesize ATP synthase, resulting in a decrease in aspartate, a precursor to pyrimidine. Furthermore, reduced CDA and NME1 gene expression impeded pyrimidine metabolism. Conversely, augmented AKR1C2 and AKR1C3 expression and elevated CDKN1A expression, which synthesizes p21, curtailed cell proliferation. Additionally, diminished TSNAX-DISC1 and CYP1B1 expression similarly restrained cell proliferation, potentially by reducing Wnt/β-catenin signaling. These findings may represent a novel therapeutic approach for patients with radioresistant triple-negative breast cancer.

Keywords: Melatonin; Metabolic profiling; Multi-omics; Ortho-topolin riboside; Potential therapeutic targets; Radioresistant; Transcriptomic profiling; Triple negative breast cancer.