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

• Published in: The international journal of biochemistry & cell biology Vol. 67; pp. 14 - 24
• Main Authors: Queiroz, Eveline A.I.F., Fortes, Zuleica B., da Cunha, Mário A.A., Barbosa, Aneli M., Khaper, Neelam, Dekker, Robert F.H.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01-10-2015
• Subjects: AMP-Activated Protein Kinases - genetics; AMP-Activated Protein Kinases - metabolism; AMPK; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; bcl-2-Associated X Protein - genetics; bcl-2-Associated X Protein - metabolism; beta-Glucans - pharmacology; Botryosphaeran; Caspase 3 - genetics; Caspase 3 - metabolism; Cell Cycle - drug effects; Cell Proliferation - drug effects; Cyclin-Dependent Kinase Inhibitor p27 - genetics; Cyclin-Dependent Kinase Inhibitor p27 - metabolism; Female; Forkhead Box Protein O3; Forkhead Transcription Factors - agonists; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; FOXO3a; Fungal Polysaccharides - pharmacology; Gene Expression Regulation, Neoplastic; Humans; Hydrogen Peroxide - pharmacology; Lasiodiplodan; MCF-7 Cells; Oxidative stress; Oxidative Stress - drug effects; Ribosomal Protein S6 Kinases, 70-kDa - genetics; Ribosomal Protein S6 Kinases, 70-kDa - metabolism; Signal Transduction; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Oxidative stress; FOXO; Lasiodiplodan; Botryosphaeran; ROS; mTOR; AMPK; BRMs; EPS; FOXO3a; TLRs; Apoptosis
• ISSN: 1357-2725; 1878-5875
• DOI: 10.1016/j.biocel.2015.08.003

•β-Glucans presented antiproliferative and pro-apoptotic effects against MCF-7 cells.•The degree of branching and triple helix conformation contributed to the β-glucans effects.•The increase in apoptosis induced by β-glucans was mediated by AMPK and FOXO3a.
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.