18β-glycyrrhetinic Acid Modulated Autophagy is Cytotoxic to Breast Cancer Cells

The development of endocrine therapy resistance in the luminal A subtype of breast cancer is related to the appearance of protective autophagy.The bioactive component from the root of licorice, 18β-glycyrrhetinic acid (18β-GA), has many antitumor properties.Whether 18β-GA can modulate autophagy to inhibit proliferation of the luminal A subtype is still unclear.The proportion of apoptosis caused by 18β-GA in MCF-7 and T-47D cells was determined using flow cytometry.The autophagy marker, LC3-II conversion, was investigated using Western blotting, and a Premo TM Tandem Autophagy Sensor Kit.We found that the concentration (150-µM) of 18β-GA caused caspase-dependent apoptosis and LC3-II accumulation or blocked autophagic flux.Moreover, 18β-GA-mediated apoptosis was improved using rapamycin but reversed by 3-methyladenine (3-MA) addition.The phosphorylation level of Jun-amino-terminal kinase (JNK) was increased significantly in the 18β-GA treatment and combined incubation using rapamycin.A JNK inhibitor (SP600125) significantly inhibited 18β-GA-mediated apoptosis, LC3-II accumulation and rescued the numbers of MCF-7 and T-47D colony formation.Especially, 18β-GA can inhibit xenograft tumor growth in BALB/c nude mice.These data indicate the combination of 18β-GA with rapamycin or 3-MA can sensitize or decrease MCF-7 and T-47D cells to 18β-GA-induced apoptosis, respectively.18β-GA modulated autophagy is cytotoxic to luminal A subtype breast cancer cells through apoptosis promotion and JNK activation.