title: Reduced signaling of PI3K-Akt and RAS-MAPK pathways is the key target for weight-loss-induced cancer prevention by dietary calorie restriction and/or physical activity.
abstract: Weight control through either dietary calorie restriction (DCR) or exercise has been associated with cancer prevention in animal models. However, the underlying mechanisms are not fully defined. Bioinformatics using genomics, proteomics and lipidomics was employed to elucidate the molecular targets of weight control in a mouse skin cancer model. SENCAR mice were randomly assigned into four groups for 10 weeks: ad-libitum-fed sedentary control, ad-libitum-fed exercise (AE), exercise but pair-fed isocaloric amount of control (PE) and 20% DCR. Two hours after topical TPA treatment, skin epidermis was analyzed by Affymetrix for gene expression, DIGE for proteomics and lipidomics for phospholipids. Body weights were significantly reduced in both DCR and PE but not AE mice versus the control. Among 39,000 transcripts, 411, 67 and 110 genes were significantly changed in DCR, PE and AE, respectively. The expression of genes relevant to PI3K-Akt and Ras-MAPK signaling was effectively reduced by DCR and PE but not AE as measured through GenMAPP software. Proteomics analysis identified ~120 proteins, with 27 proteins significantly changed by DCR, including up-regulated apolipoprotein A-1, a key antioxidant protein that decreases Ras-MAPK activity. Of the total 338 phospholipids analyzed by lipidomics, 57 decreased by PE including 5 phophatidylinositol species that serve as PI3K substrates. Although a full impact has not been determined yet, it appears that the reduction of both Ras-MAPK and PI3K-Akt signaling pathways is a cancer preventive target that has been consistently demonstrated by three bioinformatics approaches.
authors.affiliation: Department of Human Nutrition, Kansas State University, Manhattan, KS 66506.
authors.forename: Joseph
authors.initials: J
authors.lastname: Standard
authors.affiliation: Department of Human Nutrition, Kansas State University, Manhattan, KS 66506.
authors.forename: Yu
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Human Nutrition, Kansas State University, Manhattan, KS 66506.
authors.forename: Miao
authors.initials: M
authors.lastname: Yu
authors.affiliation: Department of Human Nutrition, Kansas State University, Manhattan, KS 66506.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Su
authors.affiliation: Institute for Agri-food Standards and Testing Technology, Shanghai Academy of Agricultural Sciences, Shanghai, China 201403.
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Human Nutrition, Kansas State University, Manhattan, KS 66506.
authors.forename: Jianteng
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Human Nutrition, Kansas State University, Manhattan, KS 66506.
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Human Nutrition, Kansas State University, Manhattan, KS 66506.
authors.forename: Brenee
authors.initials: B
authors.lastname: King
authors.affiliation: Institute of Animal Husbandry & Veterinary Science, Zhejiang Academy of Agricultural Sciences, Hangzhou, China 310021.
authors.forename: Lizhi
authors.initials: L
authors.lastname: Lu
authors.affiliation: Department of Biochemistry, Kansas State University, Manhattan, KS 66506.
authors.forename: John
authors.initials: J
authors.lastname: Tomich
authors.affiliation: Department of Applied Health Science, Wheaton College, Wheaton, IL 60187.
authors.forename: Richard
authors.initials: R
authors.lastname: Baybutt
authors.affiliation: Department of Human Nutrition, Kansas State University, Manhattan, KS 66506. Electronic address: wwang@ksu.edu.
authors.forename: Weiqun
authors.initials: W
authors.lastname: Wang
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics / Q000378:metabolism; D031204:Caloric Restriction; D019295:Computational Biology; D004195:Disease Models, Animal; D002149:Energy Intake; D005260:Female; D051379:Mice; D018632:Mice, Inbred SENCAR; D046228:Microarray Analysis; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D010805:Physical Conditioning, Animal; D040901:Proteomics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D012867:Skin / Q000187:drug effects / Q000473:pathology; D012878:Skin Neoplasms / Q000235:genetics / Q000517:prevention & control*; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity; D059467:Transcriptome; D015854:Up-Regulation; D015431:Weight Loss
chemical_list: D016632:Apolipoprotein A-I; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D013755:Tetradecanoylphorbol Acetate
keywords: Bioinformatics; Cancer prevention; Dietary calorie restriction; Exercise; Weigh control