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 were employed to elucidate the molecular targets of weight control in a mouse skin cancer model. SENCAR mice were randomly assigned into 4 groups for 10 weeks: ad lib-fed sedentary control, ad lib-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 upregulated 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 the reduction of both Ras-MAPK and PI3K-Akt signaling pathways are cancer preventive targets that have been consistently demonstrated by three bioinformatics approaches.

Recent advances in lipidomics for disease research

“…A study investigated the function of individual PL in cell cycle regulation, showing that 20:4‐PC oscillates during the cell cycle and delays cell cycle progression by inhibiting Akt membrane binding . Weight loss induced cancer prevention by dietary calorie restriction and/or physical activity demonstrated that the reduction of both Ras‐MAPK and PI3K‐Akt signaling pathways was a cancer preventive target .…”

Exercise-related genes analysis of Mongolian Horse

“…Further on SNPs, we analyzed functions of 440 genes of Abaga horse without 39 overlapped genes of positively selected genes between Abaga horse and Wushen horse. We focused on the enriched exercise-related pathways which referred to Metabolic pathways (Hill et al 2010), Ras signaling pathway (Shioi et al 2002; Xie et al 2007), PI3K-Akt signaling pathway (Shioi et al 2002; Luo et al 2005; Sagara et al 2012; Standard et al 2014; Song et al 2015; Liu et al 2016; Vega et al 2017), MAPK signaling pathway (Schröder et al 2011), Hippo signaling pathway (Gabriel et al 2016), Valine, leucine and isoleucine degradation (McGivney et al 2010), Cardiac muscle contraction (Do et al 2015), NF-kappa B signaling pathway (Kramer and Goodyear 2007), Arachidonic acid metabolism (Hill et al 2010), Regulation of actin cytoskeleton (Hill et al 2010; Schröder et al 2011), Insulin signaling pathway (Gim et al 2004; Hill et al 2010) and Fatty acid metabolism (Gim et al 2004; Hill et al 2010) in the 440 positively selected genes of Abaga horse that distinguished from Wushen horse (Figure 7). These enriched pathways comprised some recurrent genes (Figure 7).…”

Effects of Dietary Restriction on Cancer Development and Progression

“…According to previous studies (Xie et al 2007;Standard et al 2014), gene expression analysis of DEN-induced mice HCC cells revealed that DR restores functioning of many MAPK genes. MAPK pathway regulated by RAS promotes tumor growth and is one of the most important molecular targets for treatment of several types of cancers (Duan et al 2017).…”