Targeting AKT/mTOR Signaling Pathways During Murine Skin Tumor Promotion and the Impact of Dietary Energy Balance Manipulation

The prevalence of obesity has continued to rise over the last several decades in the United States lending to overall increases in risk for chronic diseases including many types of cancer. In contrast, reduction in energy consumption via calorie restriction (CR) has been shown to be a potent inhibitor of carcinogenesis across a broad range of species and tumor types. Previous data has demonstrated differential signaling through Akt and mTOR via the IGF-1R and other growth factor receptors across the diet-induced obesity (DIO)/CR spectrum. Furthermore, mTORC1 is known to be regulated directly via nutrient availability, supporting its role in the link between epithelial carcinogenesis and diet-induced obesity. In an effort to better understand the importance of mTORC1 in the context of both positive and negative energy balance during epithelial carcinogenesis, we have employed the use of specific pharmacological inhibitors, rapamycin (mTORC1 inhibitor) and metformin (AMPK activator) to target mTORC1 or various components of this pathway during skin tumor promotion. Two-stage skin carcinogenesis studies demonstrated that mTORC1 inhibition via rapamycin, metformin or combination treatments greatly inhibited skin tumor development in normal, overweight and obese mice. Furthermore, mechanisms by which these chemopreventive agents may be exerting their anti-tumor effects were explored. In addition, the effect of these compounds on the epidermal proliferative response was analyzed and drastic decreases in epidermal hyperproliferation and hyperplasia were found. Rapamycin also inhibited dermal inflammatory cell infiltration in a dose-dependent manner. Both compounds also blocked or attenuated TPA-induced signaling through epidermal mTORC1 as well as several downstream targets. In addition, inhibition of this pathway by metformin appeared to be, at least in part, dependent on AMPK activation in the skin. Overall, the data indicate that pharmacological strategies targeting this pathway offset the tumor-enhancing effects of DIO and may serve as possible CR mimetics. They suggest that mTORC1 contributes significantly to the process of skin tumor promotion, specifically during dietary energy balance effects. Exploiting the mechanistic information underlying dietary energy balance responsive pathways will help translate decades of research into effective strategies for prevention of epithelial carcinogenesis.

Mexico: A new heavy weight in a global world

In the last three decades, obesity has been gaining recognition as a serious public health problem in Mexico. This epidemic developed insidiously in a country that was still focused on chronic under-nutrition in the population. During that same period, macro-economic reforms projected Mexico into the global economic arena. Foreign investments, trade in goods and services, and technological transfers were promoted through participation in numerous trade agreements between Mexico and other countries. The North American Trade Agreement (NAFTA), signed in 1994, promised an integrated market between the three North American countries: Canada, the United States, and Mexico. Although these trade policies were likely to have effects on the available food supply in Mexico, this association has not been elucidated. In this case study, we examine how these trade liberalization policies may have influenced the food supply in Mexico.^ Information on the trade of food commodities between the United States and Mexico and the nature of foreign investment in Mexico was compiled using public data available through American, Mexican, and other international published reports for 1986 through 2011. After the implementation of NAFTA, an increase in trade and investments was observed between Mexico and its two North American partners, but most of the trade increase occurred between the US and Mexico. Since the liberalization of trade policies between these counties, exports of fruit and vegetables into the U.S. from Mexico have increased, while exports of cereals, fats, vegetable oils, meat, dairy products and processed foods from the U.S. into Mexico have increased. During this same time period, there has been an increase in the foreign direct investment in the food industry in Mexico, as well as changes in the types and amounts of dietary energy available on a population level. Specifically, between 1990 to 2006, the dietary energy supply per person has increased 6.1% available animal protein has increased 35.8%, and available fat has increased 18.9%.^ Thus, this case study suggests that the recent changes in food-related industries through foreign direct investment and market liberalization may be likely contributors to the obesogenic food environment in Mexico. Although this initial case study provides interesting data, whether trade liberalization policies should be considered hazardous for health as a distal determinant of the obesity epidemic needs to be further examined using a more stringent study design or further follow up of the US Mexico trade data.^