Abstract
In the complex tumor microenvironment, cancer stem cells (CSCs), a rare population of cells, are responsible for malignant tumor initiation, metastasis, drug resistance and recurrence. Controlling breast CSCs (BCSCs) using natural compounds is a novel potential therapeutic strategy for clinical cancer treatment. In this study, a mammosphere assay-guided isolation protocol including silica gel, a C18 column, gel filtration, and high-pressure liquid chromatography was used to isolate an inhibitory compound from Cynanchum auriculatum extracts. The isolated inhibitory compound was identified as caudatin. Caudatin inhibited breast cancer cell proliferation, mammosphere formation and tumor growth. Caudatin decreased the CD44+/CD24− and aldehyde dehydrogenase+ cell proportions and the levels of c-Myc, Oct4, Sox2, and CD44. Caudatin induced ubiquitin (Ub)-dependent glucocorticoid receptor (GR) degradation and blocked subsequent Yes-associated protein (YAP) nuclear accumulation and target gene transcription signals in BCSCs. These results show that the GR/YAP signaling pathway regulates BCSC formation and that caudatin may be a potential chemopreventive agent that targets breast cancer cells and CSCs.
Highlights
Cynanchum auriculatum Royle ex Wight is an Asclepiadaceae medicinal plant that is widely distributed in Asian countries, especially in China, Japan, India and Korea [1]
To isolate a human breast cancer stem cells (BCSCs) inhibitor, a mammosphere formation assay was performed with MDA-MB-231 cells treated with extracts from C. auriculatum
An isolated sample derived from C. auriculatum methanol extracts inhibited BCSCs (Figure 1B)
Summary
Cynanchum auriculatum Royle ex Wight is an Asclepiadaceae medicinal plant that is widely distributed in Asian countries, especially in China, Japan, India and Korea [1]. Pharmacological and phytochemical studies have reported that C. auriculatum has high application and economic value and displays beneficial antiviral [4], gastroprotective [5], antioxidant [6], antidepressant [7] and antitumor activities [8]. Caudatin is a type of C-21 steroid mainly isolated from C. auriculatum, which has been shown to have effective activity against cancers of different origins [9,10]. It has been reported that caudatin induces cancer cell apoptosis through C/EBP Homologous Protein (CHOP)-, p38-mitogen-activated protein kinase (MAPK)-, and c-Jun N-terminal kinase (JNK)-mediated upregulation of death receptor 5 expression [11]. Caudatin suppresses uterine cancer cells by regulating α-induced protein 1 (TNFAIP1)/Nuclear factor-κB (NF-κB) signaling [12]. Evidence of the anticancer effects of caudatin is expanding, there is no report concerning the mechanisms underlying the effects of caudatin on breast cancer stem cells (BCSCs)
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