Figure 7.

Model for REDD1 loss in RAS-driven tumorigenesis. REDD1 loss up-regulates HIF, PPARγ/CD36, and fatty acid-binding proteins (FABPs) to mediate uptake and lipid droplet storage. This effect is associated with increased fatty acid oxidation (FAO) that generates ATP as well as reducing equivalents (NADPH and GSH) through the mitochondrial Krebs (TCA) cycle, resulting in relief from RAS-induced energy stress and oxidative stress, and ultimately tumor progression. We hypothesize that combination therapies targeting the multiple metabolic nodes described herein are likely to be effective against REDD1-deficient, RAS mutant cancers.