Antiproliferative and pro-apoptotic effects of three fungal exocellular β-glucans in MCF-7 breast cancer cells is mediated by oxidative stress, AMP-activated protein kinase (AMPK) and the Forkhead transcription factor, FOXO3a

Fungal beta-D-glucans of the (1 -> 3)-type are known to exhibit direct antitumor effects, and can also indirectly decrease tumor proliferation through immunomodulatory responses. The underlying molecular mechanisms involved in decreasing tumor formation, however, are not well understood. In this study, we examined the antiproliferative role and mechanism of action of three different fungal exocellular beta-glucans in MCF-7 breast cancer cells. The beta-glucans were obtained from Botuosphaeria rhodina MAMB-05 [two botryosphaerans; (1 -> 3)(1 -> 6)-beta-D-glucan; one produced on glucose, the other on fructose] and Lasiodiplodia theobromae MMPI [lasiodiplodan; (1 -> 6)-beta-D-glucan, produced on glucose]. Using the cell proliferation-MU assay, we showed that the beta-glucans exhibited a time- and concentration-dependent antiproliferative activity (IC50, 100 mu g/ml). Markers of cell cycle, apoptosis, necrosis and oxidative stress were analyzed using flow cytomeny, RT-PCR and Western blotting. Exposure to beta-glucans increased apoptosis, necrosis, oxidative stress, mRNA expression of p53, p27 and Bax; the activity of AMP-activated protein-kinase, Forkhead transcription factor FOXO3a, Bax and caspase-3; and decreased the activity of p70S6K in MCF-7 cells. In the presence of hydrogen peroxide, the fungal beta-glucans increased oxidative stress, which was associated with reduced cell viability. We showed that these beta-glucans exhibited an antiproliferative effect that was associated with apoptosis, necrosis and oxidative stress. This study demonstrated for the first time that the apoptosis induced by beta-glucans was mediated by AMP-activated protein-kinase and Forkhead transcription factor, FOXO3a. Our findings provide novel mechanistic insights into their antiproliferative roles, and compelling evidence that these beta-glucans possess a broad range of biomodulatory properties that may prove useful in cancer treatment. (C) 2015 Elsevier Ltd. All rights reserved.