Marasmius oreades substances block NF-kappaB activity through interference with IKK activation pathway

The activation pathway of nuclear transcription factor kappa B (NF-kappaB) is a key mechanism for the progression of carcinogenesis at the molecular level. NF-kappaB is related to the promotion of cell proliferation, inhibition of apoptosis, and the enhancement of tumor metastasis and angiogenesis. Marasmius oreades culture liquid extract, which was previously shown to affect NF-kappaB activation through inhibition of the phosphorylation of the inhibitory protein kappa B (IkappaBalpha), was subjected to liquid chromatography in order to investigate the specific mechanism of action of the active moieties present in the extract. Four fractions were obtained and tested for their abilities to block NF-kappaB activation pathway at different molecular levels. All fractions showed an anti-proliferative potential with no apparent cytotoxicity on MCF7 breast cancer cell line. Two out of the four fractions strongly affected the phosphorylation of IkappaBalpha and the NF-kappaB reporter activity in MCF7 breast cancer cell line. In addition, these two fractions prevented the p65 nuclear translocation and seemed to interfere with the IkappaB kinase (IKK) activation pathway. The IKK pathway is a major cellular signaling pathway set at a crossroad leading to NF-kappaB activation by a variety of stimuli. Also, these two fractions induced apoptosis of MCF7 cells. This study adds additional valuable data to our knowledge on the anticancer potential of fungal metabolites. It is the first report showing the medicinal value of M. oreades as a natural source of low-molecular-weight bioactive substances able to affect the process of tumorogenesis through the direct blockage of NF-kappaB activation at the IKK level.