Fungal metabolite altersolanol a exhibits potent cytotoxicity against human placental trophoblasts in vitro via mitochondria-mediated apoptosis.

Abstract

Altersolanol A, a fungus-derived tetrahydroanthraquinone, has shown cytotoxic effects on multiple cancer cells. However, its reproductive toxicity in humans has not been well-addressed. The present study was aimed at investigating the cytotoxicity of altersolanol A on human placental trophoblasts including choriocarcinoma cell line JEG-3 and normal trophoblast cell line HTR-8/SVneo in vitro. The results showed that altersolanol A inhibited proliferation and colony formation of human trophoblasts, and the choriocarcinoma cells were more sensitive to the compound than the normal trophoblasts. Altersolanol A induced cell cycle arrest at G2/M phase in JEG-3 cells and S phase in HTR-8/SVneo cells, downregulated the expression of cell cycle-related checkpoint proteins, and upregulated the p21 level. Altersolanol A also promoted apoptosis in human trophoblasts via elevating the Bax/Bcl-2 ratio and decreasing both caspase-3 and caspase-9 levels. Meanwhile, altersolanol A suppressed the mitochondrial membrane potential and induced ROS production and cytochrome c release, which activated the mitochondria-mediated intrinsic apoptosis. Moreover, migration and invasion were inhibited upon altersolanol A exposure with downregulation of matrix metalloproteinase (MMP)-2 in JEG-3 cells and MMP-9 in HTR-8/SVneo cells. Mechanically, altersolanol A supplement decreased the phosphorylation of JNK, ERK, and p38, manifesting the inactivation of MAPK signaling pathway in the human trophoblasts. In conclusion, altersolanol A exhibited potential reproductive cytotoxicity against human trophoblasts via promoting mitochondrial-mediated apoptosis and inhibiting the MAPK signaling pathway.