EGF‐induced intestinal cell proliferation is dependent on loss of FOXO3 activity and increased lipid droplet density (906.1)

Abstract

The proliferation of intestinal cells, critical for homeostasis, wound healing, and sustained tumor growth, is in part controlled by EGF. The source of cellular energy required for the high metabolic needs of proliferative intestinal cells remains unclear. Triacylglycerols are stored in lipid droplets (LDs), and these neutral lipids can be a rich source of energy for various cell functions. We investigated whether intestinal epithelial cells increased intracellular energy stores by inactivating FOXO3 and altering EGF receptor (EGFR) signaling targets. Human intestinal HT29 cells, treated with EGF (10 ng/ml) with or without pharmacological inhibitors of various EGFR pathways were assessed for LD status and proliferation. In HT29 cells, EGF stimulated proliferation is associated with increased LD density while LDs depletion significantly lowers EGFR and proliferation. Moreover, depleting LDs prevent EGF mediated FOXO3 inactivation supporting dependency of LD density on FOXO3. Inhibition of EGFR reduced increased LD density, suggesting the involvement of its downstream pathways. Indeed, inhibition of phosphoinositide 3‐kinase, mTOR, and prostaglandin E2 diminishes EGF stimulated LD density. The novel mechanism of intestinal cell proliferation mediated by EGFR dependent energy from increased LD density could serve as a new therapeutic approach for intestinal wound healing or cancer treatment.Grant Funding Source: Supported by NIH ‐CA160809