Starvation, Stress Resistance, and Cancer

Abstract

Cancer cells are characterized by dysregulation in signal transduction and metabolic pathways leading to increased glucose uptake, altered mitochondrial function, and the evasion of antigrowth signals. Fasting and fasting-mimicking diets (FMDs) provide a particularly promising intervention to promote differential effects in normal and malignant cells. These effects are caused in part by the reduction in IGF-1, insulin, and glucose and the increase in IGFBP1 and ketone bodies, which generate conditions that force cancer cells to rely more on metabolites and factors that are limited in the blood, thus resulting in cell death. Here we discuss the cellular and animal experiments demonstrating the differential effects of fasting on normal and cancer cells and the mechanisms responsible for these effects.

Keywords: IGF-1; cancer; differential stress resistance; differential stress sensitization; fasting-mimicking diet; starvation.

Figure 1.. Schematic Representation of Differential Stress Resistance (DSR) and Differential Stress Sensitization (DSS) Mechanisms in Response to Fasting and Fasting-Mimicking Diets (FMDs)

In normal cells, proteins/enzymes downstream of glucose, IGF-1, and other growth factor pathways, including TOR, PKA, and AKT, are downregulated in response to fasting and FMDs. This down regulation arrests or reduces growth and promotes the activation of stress resistance genes resulting in protection against chemotherapy (DSR) and other drugs, survival, and regeneration. By contrast, cancer cells are sensitized by fasting/FMDs because of the constitutive activity of oncoproteins, which negatively regulate stress resistance and promote the generation of reactive oxygen species and cell death (DSS). The picture was drawn by using Photoshop CS6 and ChemDrawn Professional 17.