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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.
Int J Biochem Cell Biol. 2015 Oct; 67:14-24.IJ

Abstract

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.

Authors+Show Affiliations

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.Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-900, SP, Brazil.Departamento de Química, Universidade Tecnológica Federal do Paraná, Pato Branco 85503-390, PR, Brazil.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.Medical Sciences Division, Northern Ontario School of Medicine (NOSM), Lakehead University, Thunder Bay, ON, Canada P7B 5E1. Electronic address: nkhaper@nosm.ca.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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26255117

Citation

Queiroz, Eveline A I F., et al. "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." The International Journal of Biochemistry & Cell Biology, vol. 67, 2015, pp. 14-24.
Queiroz EA, Fortes ZB, da Cunha MA, et al. 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. Int J Biochem Cell Biol. 2015;67:14-24.
Queiroz, E. A., Fortes, Z. B., da Cunha, M. A., Barbosa, A. M., Khaper, N., & Dekker, R. F. (2015). 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. The International Journal of Biochemistry & Cell Biology, 67, 14-24. https://doi.org/10.1016/j.biocel.2015.08.003
Queiroz EA, et al. 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. Int J Biochem Cell Biol. 2015;67:14-24. PubMed PMID: 26255117.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Queiroz,Eveline A I F, AU - Fortes,Zuleica B, AU - da Cunha,Mário A A, AU - Barbosa,Aneli M, AU - Khaper,Neelam, AU - Dekker,Robert F H, Y1 - 2015/08/05/ PY - 2015/02/09/received PY - 2015/05/27/revised PY - 2015/08/03/accepted PY - 2015/8/10/entrez PY - 2015/8/10/pubmed PY - 2016/6/9/medline KW - AMPK KW - Apoptosis KW - Botryosphaeran KW - FOXO3a KW - Lasiodiplodan KW - Oxidative stress SP - 14 EP - 24 JF - The international journal of biochemistry & cell biology JO - Int J Biochem Cell Biol VL - 67 N2 - 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. SN - 1878-5875 UR - https://www.unboundmedicine.com/medline/citation/26255117/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_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1357-2725(15)00204-6 DB - PRIME DP - Unbound Medicine ER -