Fructose, Another Sweet for Cancer: A Context Acting Nutrient Hypothesis

Abstract

Rapidly proliferating cancer cells exhibit a high energy demand. However, their utilization of the glycolytic pathway is inefficient, leading to a compensatory effect wherein cancer cells consume ten to twenty times more glucose than normal cells. In cases where glucose availability is limited due to a poorly perfused hypoxic microenvironment, cancer cells resort to alternative energy sources, including fructose. Certain tumors have been found to rely heavily on fructose, and fructose utilization contributes to pro-tumoral signaling and increased cancer risk. Over the past 70 years, dietary fructose intake has steadily increased, resulting in a rise in obesity and metabolic syndrome, both of which elevate cancer risk. In this paper, we present compelling evidence that highlights the role of fructose and the glucose transporter GLUT5 in promoting specific types of tumors. We summarize the existing evidence and pathways through which fructose contributes to cancer metabolism, particularly in cases where glucose availability is restricted. Furthermore, we propose a hypothesis that elucidates the regulation of the lipogenic phenotype by dietary fructose intake and cellular energy status. It is important to note that the effects of fructose are contextdependent, with its tumor-promoting effects varying based on the energy status of the cell. We comprehensively analyze why targeting fructose uptake and fructolysis should be important for the management of some tumors and cancer prevention.