Abstract
The saponin fraction of Aesculus chinensis Bunge fruits (SFAC) could inhibit the invasion and migration of MDA-MB-231 cells. Among which, escin Ia showed more potent inhibition of the invasion than other five main saponin constituents. It selectively reduced the expression of LOXL2 mRNA and promoted the expression of E-cadherin mRNA, and prevented the EMT process of MDA-MB-231 cells and TNF-α/TGF-β-stimulated MCF-7 cells. Moreover, it reduced the LOXL2 level in MDA-MB-231 cells but not in MCF-7 cells. When MCF-7 cells were stimulated with TNF-α/TGF-β, transfected with LOXL2 or treated with hypoxia, escin Ia down-regulated the level of LOXL2 in MCF-7 cells. Meanwhile, escin Ia suppressed the EMT process in LOXL2-transfected or hypoxia-treated MCF-7 cells. Of interest, escin Ia did not alter the level of HIF-1α in hypoxia-induced MCF-7 cells. In TNBC xenograft mice, the metastasis and EMT of MDA-MB-231 cells were suppressed by escin Ia. In conclusion, escin Ia was the main active ingredient of SFAC for the anti-TNBC metastasis activity, and its action mechanisms involved inhibition of EMT process by down-regulating LOXL2 expression.
Highlights
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancers, which shows higher metastases and relapse rates than other types
Increasing evidence has shown that the metastasis of TNBC cells mainly involves invasion, migration and angiogenesis, and the invasion is considered as the key step in metastasis process
Invasion can be regulated by a variety of factors such as breast cancer metastasis suppressor 1 (BRMS1), E-cadherin, Keratin19, lysyl oxidase-like 2 (LOXL2), metal matrix proteinase 9 (MMP9), Orai1, stromal interaction molecule 1 (Stim1), Transforming growth factor-β (TGF-β) and vascular endothelial growth factor (VEGF)
Summary
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancers, which shows higher metastases and relapse rates than other types. TNBC is treated with chemotherapeutic agents (e.g., doxorubicin, paclitaxel and cisplatin), but its relapse rate is high in the first three years due to the development of drug resistance. Neither tamoxifen nor trastuzumab which can effectively treat other subtypes of breast cancers is effective for TNBC due to the lack of estrogen receptors (ER), progesterone receptors (PR) and human epidermal growth factor receptor 2 (HER2) [1, 2]. The conventional chemotherapy and the current targeted therapy are unsatisfactory for the treatment of TNBC, and it is urgent to explore new therapeutic measures with lower toxicity and high efficiency. Various promising researches are underway for the identification of new biologics and targeted agents for TNBC treatment, such as those about epidermal growth factor receptor (EGFR) inhibitors, vascular endothelial growth factor (VEGF) inhibitors and lysyl oxidase-like 2 (LOXL2) inhibitors. Prevention of metastasis might be an effective approach for the successful treatment of TNBC [3]
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