Abstract
BackgroundBreast cancer is still the most common malignant tumor that threatens the female’s life in the world, especially triple-negative breast cancer (TNBC), one of the most difficult subtypes. Lack of targeted therapies brings about urgent demand for novel treatments. In this study we aim to investigate the anti-tumor activity of Berberine (BBR), a Chinese plant-derived alkaloid, against the TNBC cell line MDA-MB-231 and elucidate its mechanism referring to anti-inflammation.MethodsCell inhibition rate was measured by Cell Proliferation Assay, the cytotoxic effects was detected by Lactate dehydrogenase (LDH) leakage assay, the colony formation and migration potential were evaluated by colony formation assay and wound healing assay, the release of inflammatory cytokines was detected by EMD multifactor detection, and alterations of proteins and genes related to the NLR family pyrin domain containing 3 (NLRP3) inflammasome pathway were analyzed using western blotting and real-time Polymerase Chain Reaction (PCR).ResultsBBR reduce the viability of MDA-MB-231 cells and increased the release of LDH from the cells in a dose-dependent manner, with and inhibition of colony formation potential and migration of the cells. BBR also caused a marked reduction in the secretion of proinflammatory cytokines, Interleukin-1α (IL-1α), Interleukin-1β (IL-1β), Interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). Besides, a down-regulated behavior was observed with the expression of P2X purinoceptor 7 (P2X7), NLRP3, pro-caspase-1, apoptosis-associated speck-like protein containing a caspase-activation and recruitment domain (ASC), caspase-1 p20, Interleukin-18 (IL-18), IL-1β proteins and NLRP3, Caspase-1 and ASC mRNAs in the NLRP3 inflammasome cascade.ConclusionsOur results confirmed that BBR can effectively affect both tumor outgrowth and spontaneous metastasis in TNBC, and that we identified a new mechanism associated with inhibition the NLRP3 inflammasome pathway, suggesting its potential therapeutic relevance in clinical use.
Highlights
Breast cancer is still the most common malignant tumor that threatens the female’s life in the world, especially triple-negative breast cancer (TNBC), one of the most difficult subtypes
We identified a new potential mechanism by which BBR inhibits the growth of human breast cell line MDA-MB-231 associated with inhibition of the NLR family pyrin domain containing 3 (NLRP3) inflammasome pathway
Antiproliferative and cytotoxic effects of BBR First, we examined the growth inhibitory effects of BBR using the MTS cell proliferation assay in human breast cancer cell line MDA-MB-231
Summary
Breast cancer is still the most common malignant tumor that threatens the female’s life in the world, especially triple-negative breast cancer (TNBC), one of the most difficult subtypes. There would be a series of pro-inflammatory mediators, for instance, the cytokines, chemokines and transcriptional factors secreted from the cancerous cells, on the other hand, these critical inflammation-related components, in turn, were proved to be the core molecular players in regulating signaling pathways and processes involved in oncogenesis [9]. The NLR family pyrin domain containing 3 (NLRP3) inflammasome, composed by NLRP3 oligomers and apoptosis-associated speck-like (ASC) adapter protein, is a key innate immune pathway through triggering the activation of caspase-1, leading to the processing of interleukin-1 beta (IL-1β) and IL-18, as well as inducing of pyroptosis and malignant transformation [10, 11], and have been proved to take part in the genesis and development of several inflammatory disorders, including inflammatory bowel disease (IBD) [12], pancreatitis [13], and may increase the risk of cancer [14, 15]. Targeting the NLRP3 inflammasome pathway has opened the door for novel strategy in cancer prevention and treatment
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