Loss of the Transcription Factor FoxM1 in colorectal cancer cells exposed to prenylated xanthones isolated from Metaxya rostrata

Natural compounds and their derivatives are an important source of anti-cancer agents. The tree fern Metaxya rostrata C.Presl (Metaxyaceae) is widespread in the rainforests of Central and South America, where suspensions of the dried rhizome in water are orally administered against intestinal ulcers or tumors. An activity-guided study led to the isolation of structurally related xanthones. Two of them, 2-deprenyl-rheediaxanthone B (XB) and 2-deprenyl-7-hydroxy-rheediaxanthone B (OH-XB) were analysed and showed cytotoxic activity at concentrations < 10 µM. Both induced active cell death by distinct mechanisms [1]. Our study detected suppression of the transcription factor FoxM1 as the common target. Protein as well as mRNA levels were decreased after treatment with both xanthones. Knockdown of FoxM1 by siRNA interference decreased the cytotoxic effect and xanthone-induced caspase activity in SW480 colorectal cancer cells. Comparison with additional cell lines (HCT116, Caco-2, HT29 and DLD1) demonstrated decreased FoxM1 mRNA and protein levels as well as induction of caspase activity in all except HT29. HT29 cells contained no detectable FoxM1 protein and were insensitive to both, XB and OH-XB. There was no difference in the baseline FoxM1 mRNA level between HT29 and the other cell lines. Therefore, ongoing experiments explore differences in FoxM1 protein stability in compound-exposed and control cultures.

• References

• 1 Mittermair E, Krenn L, Marian B. Prenylated xanthones from Metaxya rostrata suppress FoxM1 and induce active cell death by distinct mechanisms. Phytomedicine. 2019 in press