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.

Autor: Queiroz EA; Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-900, SP, Brazil; Biorefining Research Institute (BRI), Lakehead University, Thunder Bay, ON, Canada P7B 5E1; Medical Sciences Division, Northern Ontario School of Medicine (NOSM), Lakehead University, Thunder Bay, ON, Canada P7B 5E1., Fortes ZB; Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-900, SP, Brazil., da Cunha MA; Departamento de Química, Universidade Tecnológica Federal do Paraná, Pato Branco 85503-390, PR, Brazil., Barbosa AM; Biorefining Research Institute (BRI), Lakehead University, Thunder Bay, ON, Canada P7B 5E1; Biorefining and Biotechnology Consultancy, Rua João Huss 200, Gleba Palhano, CEP 86050-490 Londrina, PR, Brazil., Khaper N; Medical Sciences Division, Northern Ontario School of Medicine (NOSM), Lakehead University, Thunder Bay, ON, Canada P7B 5E1. Electronic address: nkhaper@nosm.ca., Dekker RF; Biorefining Research Institute (BRI), Lakehead University, Thunder Bay, ON, Canada P7B 5E1; Biorefining and Biotechnology Consultancy, Rua João Huss 200, Gleba Palhano, CEP 86050-490 Londrina, PR, Brazil. Electronic address: rdekker@lakeheadu.ca.
Jazyk: angličtina
Zdroj: The international journal of biochemistry & cell biology [Int J Biochem Cell Biol] 2015 Oct; Vol. 67, pp. 14-24. Date of Electronic Publication: 2015 Aug 05.
DOI: 10.1016/j.biocel.2015.08.003
Abstrakt: Fungal β-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 β-glucans in MCF-7 breast cancer cells. The β-glucans were obtained from Botryosphaeria rhodina MAMB-05 [two botryosphaerans; (1→3)(1→6)-β-d-glucan; one produced on glucose, the other on fructose] and Lasiodiplodia theobromae MMPI [lasiodiplodan; (1→6)-β-d-glucan, produced on glucose]. Using the cell proliferation-MTT assay, we showed that the β-glucans exhibited a time- and concentration-dependent antiproliferative activity (IC50, 100μg/ml). Markers of cell cycle, apoptosis, necrosis and oxidative stress were analyzed using flow cytometry, RT-PCR and Western blotting. Exposure to β-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 β-glucans increased oxidative stress, which was associated with reduced cell viability. We showed that these β-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 β-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 β-glucans possess a broad range of biomodulatory properties that may prove useful in cancer treatment.
(Copyright © 2015 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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