180-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, 180-glycyrrhetinic acid (180-GA), has many antitumor properties. Whether 180-GA can modulate autophagy to inhibit proliferation of the luminal A subtype is still unclear. The proportion of apoptosis caused by 180-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 PremoTM Tandem Autophagy Sensor Kit. We found that the concentration (150-mu M) of 180-GA caused caspase-dependent apoptosis and LC3-II accumulation or blocked autophagic flux. Moreover, 180-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 180-GA treatment and combined incubation using rapamycin. A JNK inhibitor (SP600125) significantly inhibited 180-GA-mediated apoptosis, LC3-II accumulation and rescued the numbers of MCF-7 and T-47D colony formation. Especially, 180-GA can inhibit xenograft tumor growth in BALB/c nude mice. These data indicate the combination of 180-GA with rapamycin or 3-MA can sensitize or decrease MCF-7 and T-47D cells to 180-GA-induced apoptosis, respectively. 180-GA modulated autophagy is cytotoxic to luminal A subtype breast cancer cells through apoptosis promotion and JNK activation.