Calycosin stimulates the proliferation of endothelial cells, but not breast cancer cells, via a feedback loop involving RP11-65M17.3, BRIP1 and ERα

Abstract

It is widely accepted that estrogen can be replaced by phytoestrogens to treat postmenopausal cardiovascular disease and possibly decrease the risk of breast cancer. However, few studies have investigated the effects of phytoestrogens on vascular endothelial cells (ECs). In the present study, we show that the phytoestrogen calycosin (20 μM) stimulated the proliferation of ECs (HUVECs and HMEC-1) but inhibited the growth of breast cancer cells (BCCs) expressing ERα (MCF-7 and T47D). Here we provide evidence for the presence of a positive feedback loop between ERα and long noncoding RNA RP11-65M17.3 in both normal and cancer cells, and calycosin stimulated this feedback loop in ECs but decreased RP11-65M17.3 expression in BCCs. Subsequently, the calycosin-induced activation of this loop decreased the expression of the target of BRIP1 (BRCA1 interacting protein C-terminal helicase 1), increased the phosphorylation of Akt and ERK1/2, and finally inhibited the cleavage of PARP-1 in ECs. In nude mice bearing MCF-7 xenografts, calycosin did not stimulate tumor growth as strongly as 17β-estradiol. Together, these results suggest that calycosin promotes the proliferation of ECs, and notable inhibits the growth of BCCs. A possible reason for these results is the involvement of a feedback loop between ERα and RP11-65M17.3.

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“…Following a 48h incubation with 10nM 17-estradiol DNA synthesis had increased by 101%, (figure 2). In comparison, the stimulation of T47D and MCF7 cells by 17-estradiol was more modest at 34% and 17% respectively, which is in line with previous studies [34].…”

Unveiling the potential anti‐cancer activity of calycosin against multivarious cancers with molecular insights: A promising frontier in cancer research

“…Although calycosin offers many medicinal benefits, the human body may experience only minor adverse effects or harmful responses. Calycosin favors cancer cells when it is present in modest concentrations, including promoting the growth of cancer cells, reducing apoptosis, and downregulating ERK 1 and 2 61 . In vivo study also showed that calycosin stimulates a dramatic increase in urinary weight 29 .…”

“…Calycosin favors cancer cells when it is present in modest concentrations, including promoting the growth of cancer cells, reducing apoptosis, and downregulating ERK 1 and 2. 61 In vivo study also showed that calycosin stimulates a dramatic increase in urinary weight. 29 According to previous research, calycosin promotes angiogenesis in zebrafish larvae and human umbilical vein endothelial cells (HUVEC) both in vitro and in vivo.…”

“…60 A high dose of calycosin (150 μM) tends to act against cancer by reducing its capacity to migrate and invade, while at low concentrations (20 μM) has been proven to stop the development of cancerous cells and proliferation with inducing apoptosis. 61 Moreover, calycosin inhibited the proliferation, invasion, and migration of cancer cells through decreasing MMP-2, MMP-9, and CD147 levels through downregulating BATF (basic leucine zipper ATF-like transcription factor) expression and TGFβ1 (transforming growth factor 1) expression. 62 In vitro study with a low concentration of calycosin has shown decreasing through induction of apoptosis of Bcl-2 (Bcell lymphoma 2) and a decrease in Bax (Bcl-2-like protein 4).…”

“…In another study, it has shown the activity of calycosin suppresses some cancerous features like cell viability, migration, and invasion through downregulating Foxp3 (forkhead box P3), VEGF (vascular endothelial growth factor), and MMP‐9 (matrix metalloproteinase‐9) in MCF‐7, T‐47D cell lines for breast cancer 60 . A high dose of calycosin (150 μM) tends to act against cancer by reducing its capacity to migrate and invade, while at low concentrations (20 μM) has been proven to stop the development of cancerous cells and proliferation with inducing apoptosis 61 . Moreover, calycosin inhibited the proliferation, invasion, and migration of cancer cells through decreasing MMP‐2, MMP‐9, and CD147 levels through downregulating BATF (basic leucine zipper ATF‐like transcription factor) expression and TGFβ1 (transforming growth factor 1) expression 62 .…”