Energy balance and carcinogenesis: underlying pathways and targets for intervention.
Division of Nutritional Sciences, University of Texas, Austin, TX 78712, USA. Current cancer drug targets
(Impact Factor: 3.52).
The prevalence of obesity, an established epidemiologic risk factor for many cancers, has risen steadily for the past several decades in the U.S. Particularly alarming are the increasing rates of obesity among children, portending continuing increases in the rates of obesity and obesity-related cancers for many years to come. Unfortunately, the mechanisms underlying the association between obesity and cancer are not well understood. In particular, the effects and mechanistic targets of interventions that modulate energy balance, such as reduced calorie diets and physical activity, on the carcinogenesis process have not been well characterized. The purpose of this review is to provide a strong foundation for future mechanistic-based research in this area by describing key animal and human studies of energy balance modulations involving diet, exercise, or pharmaceutical agents and by focusing on the interrelated pathways affected by alterations in energy balance. Particular attention in this review is placed on the components of the insulin/IGF-1/Akt pathway, which has emerged as a predominant target for disrupting the obesity-cancer link. Also discussed is the promise of global approaches, including genomics, proteomics, and metabolomics, for the elucidation of energy balance-responsive pathways. The ultimate goal of this work is to provide the missing mechanistic information necessary to identify targets for the prevention and control of cancers related to or caused by excess body weight.
Available from: Dong-Sung Lee
- "However, the effects of AR on adipocyte differentiation have not yet been investigated. Obesity is a serious health problem and is related to the development of diseases such as type 2 diabetes, dyslipidemias , atherosclerosis, and even some cancers    . At the cellular level, obesity is characterized by increases in the number and volume of adipocytes, the primary storage site for energy in animals and humans. "
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ABSTRACT: The rhizome of Alisma orientale (Alismatis rhizome) has been used in Asia for promoting diuresis to eliminate dampness from the lower-jiao and to expel heat. In this study, an ethanol extract of the rhizome of Alisma orientale (AOE) was prepared and its effects on adipocyte differentiation of OP9 cells were investigated. Treatment with AOE in a differentiation medium for 5 days resulted in dose-dependent inhibition of lipid droplet formation in OP9 cells. Furthermore, AOE significantly inhibited adipocyte differentiation by downregulating the expression of the master transcription factor of adipogenesis, peroxisome proliferation-activity receptor γ (PPAR γ ), and related genes, including CCAAT/enhancer binding protein β (C/EBP β ), fatty acid-binding protein (aP2), and fatty acid synthase (FAS). AOE exerted its inhibitory effects primarily during the early adipogenesis stage (days 1-2), at which time it also exerted dose-dependent inhibition of the expression of C/EBP β , a protein related to the inhibition of mitotic clonal expansion. Additionally, AOE decreased the expression of autophagy-related proteins, including beclin 1, and the autophagy-related genes, (Atg) 7 and Atg12. Our results indicate that AOE's inhibitory effects on adipocyte differentiation of OP9 cells are mediated by reduced C/EBP β expression, causing inhibition of mitotic clonal expansion and autophagy.
Evidence-based Complementary and Alternative Medicine 06/2014; 2014(11):415097. DOI:10.1155/2014/415097 · 1.88 Impact Factor
- "In addition, human studies have established the positive association between IGF-1 levels and colon cancer risk , , . Finally, both in vitro and animal studies demonstrate the ability of IGF-1 to increase colon tumor cell growth , , . "
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ABSTRACT: Obesity is an established colon cancer risk factor, while preventing or reversing obesity via a calorie restriction (CR) diet regimen decreases colon cancer risk. Unfortunately, the biological mechanisms underlying these associations are poorly understood, hampering development of mechanism-based approaches for preventing obesity-related colon cancer. We tested the hypotheses that diet-induced obesity (DIO) would increase (and CR would decrease) colon tumorigenesis in the mouse azoxymethane (AOM) model. In addition, we established that changes in inflammatory cytokines, growth factors, and microRNAs are associated with these energy balance-colon cancer links, and thus represent mechanism-based targets for colon cancer prevention. Mice were injected with AOM once a week for 5 weeks and randomized to: 1) control diet; 2) 30% CR diet; or 3) DIO diet. Mice were euthanized at week 5 (n = 12/group), 10 (n = 12/group), and 20 (n = 20/group) after the last AOM injection. Colon tumors were counted, and cytokines, insulin-like growth factor 1 (IGF-1), IGF binding protein 3 (IGFBP-3), adipokines, proliferation, apoptosis, and expression of microRNAs (miRs) were measured. The DIO diet regimen induced an obese phenotype (∼36% body fat), while CR induced a lean phenotype (∼14% body fat); controls were intermediate (∼26% body fat). Relative to controls, DIO increased (and CR decreased) the number of colon tumors (p = 0.01), cytokines (p<0.001), IGF-1 (p = 0.01), and proliferation (p<0.001). DIO decreased (and CR increased) IGFBP-3 and apoptosis (p<0.001). miRs including mir-425, mir-196, mir-155, mir-150, mir-351, mir-16, let-7, mir34, and mir-138 were differentially expressed between the dietary groups. We conclude that the enhancing effects of DIO and suppressive effects of CR on colon carcinogenesis are associated with alterations in several biological pathways, including inflammation, IGF-1, and microRNAs.
PLoS ONE 04/2014; 9(4):e94765. DOI:10.1371/journal.pone.0094765 · 3.23 Impact Factor
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ABSTRACT: An increasing number of men and women are being diagnosed with cancer and many cancer survivors are seeking lifestyle-based approaches to improve survival. The American Cancer Society issued nutrition and physical activity recommendations for cancer survivors in 2006. This article discusses these guidelines, including more recent publications regarding obesity, exercise, diet, and nutrient supplement use in relation to cancer outcomes including survival. Observational data strongly indicate that obesity, weight gain, and physical inactivity are adverse prognostic factors, although data on diet or supplement use in relation to cancer survival are more limited and inconsistent. Randomized trials of lifestyle interventions in survivors are also very limited at present. Although there are major research gaps in the literature on nutrition and physical activity for cancer survivors, the available evidence to date suggests that physicians should be familiar with current guidelines and discuss them with their patients as an important strategy to improve long-term survival.
The Cancer Journal 11/2008; 14(6):435-41. DOI:10.1097/PPO.0b013e31818daeee · 4.24 Impact Factor
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