Activation of pro-survival metabolic networks by 1,25(OH) 2 D 3 does not hamper the sensitivity of breast cancer cells to chemotherapeutics

摘要: We have previously identified 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the bioactive form of vitamin D3, as a potent regulator energy-utilization and nutrient-sensing pathways in prostate cancer cells. In current study, we investigated effects 1,25(OH)2D3 on breast (BCa) cell metabolism using lines representing distinct molecular subtypes, luminal (MCF-7 T-47D), triple-negative BCa (MDA-MB-231, MDA-MB-468, HCC-1143). 1,25(OH)2D3’s effect was evaluated by employing combination real-time measurements glycolysis/oxygen consumption rates biosensor chip system, GC/MS-based metabolomics, gene expression analysis, assessment overall energy levels. The influence treatment energy-related signaling molecules immunoblotting. show that significantly induces activity pentose phosphate pathway enzyme glucose-6-phosphate dehydrogenase (G6PD) all lines, however differentially influences glycolytic respiratory same Although found to induce seemingly anti-oxidant responses MCF-7 cells, such increased intracellular serine levels, reduce its putative target thioredoxin-interacting protein (TXNIP), reactive oxygen species levels were be elevated. Serine accumulation 1,25(OH)2D3-treated cells not hamper efficacy chemotherapeutics, including 5-fluorouracil. Detailed analyses nature TXNIP’s regulation included genetic pharmacological inhibition metabolic enzymes AMP-activated kinase G6PD, well studying ITCH (E3 ubiquitin ligase)-TXNIP interaction. While these investigations demonstrated minimal involvement observed non-canonical TXNIP, estrogen receptor (ER) tamoxifen mirrored reduction TXNIP 1,25(OH)2D3, demonstrating latter’s negative ER is potential mechanism modulation. Altogether, propose contributes anti-cancer combining with drugs targeting networks tumor may lead synergistic effects.