Berberine exhibits antitumor effects by activating autophagy and apoptosis in anaplastic thyroid carcinoma cells by regulating ROS and the PI3K/AKT/mTOR signaling pathways

Abstract Anaplastic thyroid carcinoma (ATC) is the most lethal thyroid carcinoma. Doxorubicin (DOX) is the only drug approved for anaplastic thyroid cancer treatment, but its clinical use is restricted due to irreversible tissue toxicity. Berberine (BER), an isoquinoline alkaloid extracted from Coptidis Rhizoma, has been proposed to have antitumor activity in many cancers. However, the underlying mechanisms by which BER regulates apoptosis and autophagy in ATC remain unclear. Thus, the present study aimed to assess the therapeutic effect of BER in CAL-62 and BHT-101 cells as well as the underlying mechanisms. In addition, we assessed the antitumor effects of a combination of BER and DOX in ATC cells. The present results showed that BER significantly inhibited cell growth and induced apoptosis in ATC cells. BER treatment also significantly upregulated the expression of LC3B-II and increased the number of GFP-LC3 puncta in ATC cells, suggesting that BER induced a high level of autophagy. Inhibition of autophagy by 3-methyladenine (3-MA) suppressed BER-induced autophagic cell death, which confirmed the anticancer role of autophagy induced by BER. Moreover, BER induced the generation of reactive oxygen species (ROS). N-acetylcysteine (NAC), a potential ROS scavenger, substantially suppressed the expression of autophagy-regulated proteins and apoptosis proteins induced by BER. Moreover, BER and DOX cooperated to promote apoptosis and autophagy in ATC cells. Mechanistically, we demonstrated that BER regulated the autophagy and apoptosis of human ATC cells through the PI3K/AKT/mTOR pathways. Taken together, the present findings indicated that BER induces apoptosis and autophagic cell death by activating ROS and regulating the PI3K/AKT/mTOR signaling pathway.