title: Polyphenolics from mango (Mangifera indica L.) suppress breast cancer ductal carcinoma in situ proliferation through activation of AMPK pathway and suppression of mTOR in athymic nude mice.
abstract: The objective of this study was to assess the underlying mechanisms of mango polyphenol decreased cell proliferation and tumor volume in ductal carcinoma in situ breast cancer. We hypothesized that mango polyphenols suppress signaling along the AKT/mTOR axis while up-regulating AMPK. To test this hypothesis, mango polyphenols (0.8 mg gallic acid equivalents per day) and pyrogallol (0.2 mg/day) were administered for 4 weeks to mice xenografted with MCF10DCIS.com cells subcutaneously (n=10 per group). Tumor volumes were significantly decreased, both mango and pyrogallol groups displayed greater than 50% decreased volume compared to control. There was a significant reduction of phosphorylated protein levels of IR, IRS1, IGF-1R, and mTOR by mango; while pyrogallol significantly reduced the phosphorylation levels of IR, IRS1, IGF-1R, p70S6K, and ERK. The protein levels of Sestrin2, which is involved in AMPK-signaling, were significantly elevated in both groups. Also, mango significantly elevated AMPK phosphorylation and pyrogallol significantly elevated LKB1 protein levels. In an in vitro model, mango and pyrogallol increased reactive oxygen species (ROS) generation and arrested cells in S phase. In silico modeling indicates that pyrogallol has the potential to bind directly to the allosteric binding site of AMPK, inducing activation. When AMPK expression was down-regulated using siRNA in vitro, pyrogallol reversed the reduced expression of AMPK. This indicates that pyrogallol not only activates AMPK, but also increases constitutive protein expression. These results suggest that mango polyphenols and their major microbial metabolite, pyrogallol, inhibit proliferation of breast cancer cells through ROS-dependent up-regulation of AMPK and down-regulation of the AKT/mTOR pathway.
authors.affiliation: Interdisciplinary Program of Toxicology, Texas A&M University, College station, TX.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Nemec
authors.affiliation: Department of Nutrition and Food Science, Texas A&M University, College station, TX.
authors.forename: Hyemee
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Biology, Texas A&M University, College station, TX.
authors.forename: Alexandria B
authors.initials: AB
authors.lastname: Marciante
authors.affiliation: Department of Nutrition and Food Science, Texas A&M University, College station, TX.
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Barnes
authors.affiliation: Interdisciplinary Program of Toxicology, Texas A&M University, College station, TX.
authors.forename: Erik D
authors.initials: ED
authors.lastname: Hendrick
authors.affiliation: Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR.
authors.forename: William H
authors.initials: WH
authors.lastname: Bisson
authors.affiliation: Department of Nutrition and Food Science, Texas A&M University, College station, TX.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Talcott
authors.affiliation: Interdisciplinary Program of Toxicology, Texas A&M University, College station, TX; Department of Nutrition and Food Science, Texas A&M University, College station, TX. Electronic address: smtalcott@tmau.edu.
authors.forename: Susanne U
authors.initials: SU
authors.lastname: Mertens-Talcott
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000032:analysis / Q000737:chemistry / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000178:diet therapy* / Q000378:metabolism / Q000473:pathology; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000178:diet therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019587:Dietary Supplements / Q000032:analysis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D031022:Mangifera; D008819:Mice, Nude; D010766:Phosphorylation; D010936:Plant Extracts / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D059808:Polyphenols / Q000009:adverse effects / Q000032:analysis / Q000627:therapeutic use*; D011499:Protein Processing, Post-Translational; D011748:Pyrogallol / Q000009:adverse effects / Q000032:analysis / Q000627:therapeutic use; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000819:agonists / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C501277:Mangifera indica extract; D010936:Plant Extracts; D059808:Polyphenols; D017382:Reactive Oxygen Species; D011748:Pyrogallol; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases
keywords: Breast cancer; Ductal carcinoma in situ; Mango; Polyphenols; Xenograft