Reversal of epithelial to mesenchymal transition in triple negative breast cancer through epigenetic modulations by dietary flavonoid Galangin and its combination with SAHA.
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引用次数: 0
Abstract
Background: TNBC is an aggressive metastatic cancer that poses considerable treatment challenges because of its acquired drug resistance towards the existing targeted and hormonal therapies. The epigenetic modulation including HDACs triggers the EMT in TNBC which produces a more aggressive tumor phenotype. Chemotherapy and radiotherapy cause severe side effects which make treatment complex and challenging. To avoid these serious side effects and boost the effectiveness of current anti-cancer medications, plant flavonoids have been investigated.
Aim of the study: The present investigation is aimed to understand the role of dietary flavonoid Gal in the modulation of epigenetic regulators such as HDACs and HATs and their impact on the reversal of the EMT process in TNBCs.
Methodology: Here, we have examined the anti-TNBC potential of Gal alone and in combination with SAHA by performing series of in vitro cell culture assays such MTT, migration and invasion, cell cycle regulation, ROS generation & mitochondrial dysfunction, nuclear fragmentation & apoptosis induction etc. The expression profiles of epigenetic regulators, apoptosis regulating proteins, and EMT markers were analysed by performing transcriptomic and proteomic studies. The in vivo efficacy of Gal was studied using BALB/c mice xenograft model studies.
Results: At IC50 = 50 µM/mL, Gal significantly inhibited the cell proliferation, migration, and invasion, arrested cell cycle at sub G0/G1 phases, generated ROS, reduced MMP and induced apoptosis in MDA-MB-231. Transcriptomic, proteomic, and calorimetric analysis revealed that Gal has potential to downregulate the expression of HDAC1/HDAC3 and elevate the expression levels of HAT. Gal also modulated the process of EMT by downregulating the mesenchymal markers and upregulating the epithelial marker. The synergistic mechanism of Gal and SAHA against the TNBCs was elucidated by understanding the expression levels of epigenetic regulators & EMT markers. Interestingly, Gal increased the expression of tumour suppressor protein pTEN and suppressed the expression of AKT, PI3K, and mTOR proteins involved in the cancer proliferation pathway. Gal also demonstrated impressive antitumor effect under in vivo settings.
Conclusion: In-vitro and In vivo studies confirmed Gal's potent anticancer efficacy and highlighted its potential as a promising therapeutic agent that possibly can be used with conventional chemotherapy against TNBC.
期刊介绍：
Cell Communication and Signaling (CCS) is a peer-reviewed, open-access scientific journal that focuses on cellular signaling pathways in both normal and pathological conditions. It publishes original research, reviews, and commentaries, welcoming studies that utilize molecular, morphological, biochemical, structural, and cell biology approaches. CCS also encourages interdisciplinary work and innovative models, including in silico, in vitro, and in vivo approaches, to facilitate investigations of cell signaling pathways, networks, and behavior.
Starting from January 2019, CCS is proud to announce its affiliation with the International Cell Death Society. The journal now encourages submissions covering all aspects of cell death, including apoptotic and non-apoptotic mechanisms, cell death in model systems, autophagy, clearance of dying cells, and the immunological and pathological consequences of dying cells in the tissue microenvironment.
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