Calorie restriction and cancer prevention: metabolic and molecular mechanisms

Abstract

An important discovery of recent years has been that lifestyle and environmental factors affect cancer initiation, promotion and progression, suggesting that many malignancies are preventable. Epidemiological studies strongly suggest that excessive adiposity, decreased physical activity, and unhealthy diets are key players in the pathogenesis and prognosis of many common cancers. In addition, calorie restriction (CR), without malnutrition, has been shown to be broadly effective in cancer prevention in laboratory strains of rodents. Adult-onset moderate CR also reduces cancer incidence by 50% in monkeys. Whether the antitumorigenic effects of CR will apply to humans is unknown, but CR results in a consistent reduction in circulating levels of growth factors, anabolic hormones, inflammatory cytokines and oxidative stress markers associated with various malignancies. Here, we discuss the link between nutritional interventions and cancer prevention with focus on the mechanisms that might be responsible for these effects in simple systems and mammals with a view to developing chemoprevention agents.

Fig. 1. Effects of excessive calorie intake and adiposity on hormones and growth-factor production and cell proliferation

Excessive calorie intake and a sedentary lifestyle promote hypertrophy of adipose tissue, reduce adiponectin production, and increase circulating free fatty acids (FFA) and inflammation, leading to insulin resistance and compensatory hyperinsulinemia. Increased serum insulin concentration causes a reduction in hepatic synthesis of insulin-like growth factor binding protein 1 (IGFBP1) and steroid hormone binding globulin (SHBG), that leads to increased bioavailability of insulin growth factor 1 (IGF-1) and sex hormones. Adipose tissue is also a major source of extra-glandular estrogens. Chronically elevated circulating levels of insulin, IGF-1, sex hormones and inflammatory cytokines promote cellular proliferation, genomic instability, and inhibit apoptosis in many cell types.

Fig. 2. Mechanisms for cancer prevention by calorie restriction

CR causes several key metabolic/hormonal adaptations, that alter the expression of several genes and signaling pathways (up-regulation of certain genes/signaling pathways and down-regulation of others as indicated by the arrows), which produce major cellular adaptations (e.g. a reduction in cell proliferation, increased removal of damaged organelles or cells via autophagy or apoptosis, up-regulation of DNA repair systems and genomic stability) that result in a reduced cancer incidence (see the text). T3 = triiodothyronine; PI3K = phosphatidylinositol-3 kinase; AKT = kinase AKT, also known as protein kinase B; S6K1 = ribosomal S6 protein kinase 1; mTOR = mammalian target of rapamycin; MAPK = mitogen-activated protein kinase; NRF2 = transcription factors NF-E2-related factor 2; SIRT-1 = silent mating type information regulation 2 homolog 1; AMPK = adenosine monophosphate (AMP)–activated protein kinase; FOXO = Forkhead transcription factors; PTEN = phosphatase and tensin homolog.

Fig. 3. Pro-aging and pro-cancer pathways in yeast and mice

Similar pathways, including Ras, Tor, S6 kinase (S6K), adenylate cyclase (AC), and PKA, have been shown to promote aging in both yeast and mice. In yeast, CR causes the down-regulation of these proteins, which promote DNA mutations by reducing the activity of stress resistance transcription factors including Msn2/4 and Gis1 and subsequently increasing the level of superoxide and the activity of error-prone polymerases (Rev1, etc). In yeast, this DNA damage-promoting mode can occur largely independently of cell division. In mice, orthologues of yeast Tor, S6K, AC, and PKA promote aging but are also components of some of the most common oncogenic pathways. CR reduces IGF-I and consequently can reduce the activity of protein functioning downstream of IGF-IR including Tor and S6K. Activation of Tor and S6K but also of AC and PKA may promote DNA damage and cancer in part by promoting cell growth and inhibiting apoptosis in damaged cells and in part by promoting aging and genomic instability independently of the rate of cell growth. These pathways may also contribute to cancer and metastases by affecting inflammation and the cellular environment of the malignant and pre-cancerous cells. The mechanisms connecting IGF-I signaling pathways and cancer in mammals are poorly understood but may involve mechanisms similar to those identified in yeast (147).