Epidermal growth factor receptor mediated proliferation depends on increased lipid droplet density regulated via a negative regulatory loop with FOXO3/Sirtuin6

Abstract

The proliferation of colon cancer cells is mediated in part by epidermal growth factor receptor (EGFR) signaling and requires sustained levels of cellular energy to meet its high metabolic needs. Intracellular lipid droplets (LDs) are a source of energy used for various cellular functions and they are elevated in density in human cancer, yet their regulation and function are not well understood. Here, in human colon cancer cells, EGF stimulates increases in LD density, which depends on EGFR expression and activation as well as the individual cellular capacity for lipid synthesis. Increases in LDs are blockaded by inhibition of PI3K/mTOR and PGE2 synthesis, supporting their dependency on select upstream pathways. In colon cancer cells, silencing of the FOXO3 transcription factor leads to down regulation of SIRT6, a negative regulator of lipid synthesis, and consequent increases in the LD coat protein PLIN2, revealing that increases in LDs depend on loss of FOXO3/SIRT6. Moreover, EGF stimulates loss of FOXO3/SIRT6, which is blockaded by the inhibition of upstream pathways as well as lipid synthesis, revealing existence of a negative regulatory loop between LDs and FOXO3/SIRT6. Elevated LDs are utilized by EGF treatment and their depletion through the inhibition of lipid synthesis or silencing of PLIN2 significantly attenuates proliferation. This novel mechanism of proliferative EGFR signaling leading to elevated LD density in colon cancer cells could potentially be therapeutically targeted for the treatment of tumor progression.

An Overview of Lipid Droplets in Cancer and Cancer Stem Cells

“…PLIN2 is a ubiquitous mainly associated LD protein, particularly abundant in the liver [ 42 ], whose expression is positively correlated with TAG levels and LD formation [ 43 ]. During adipogenic differentiation of 3T3-L1 preadipocytes, PLIN2 is replaced by PLIN1 [ 44 ].…”

“…These effects were positively mediated by the EGFR-induced activation of the PI3K/mTOR pathway and of PGE2 synthesis and negatively mediated by the inactivation (loss) of FOXO/SIRT6 tumor suppressor factors. However, the degree of these effects varied depending on cell line [ 43 ]. PI3K is an upstream regulator of FOXO activity; thus, this work supports a potential regulative role of this axis in modulating LD content in cancer cells and suggests a novel molecular link between LDs and tumor growth.…”

Lipid Droplets: A Key Cellular Organelle Associated with Cancer Cell Survival under Normoxia and Hypoxia

“…This increased LD level associates with progression of CRC. A very recent study has shown that this FOXO3-SIRT6 axis-driven regulation of CRC cell proliferation via LD production can be controlled by cellular signaling associated with cell surface epidermal growth factor receptor (EGFR) [ 76 ]. It has recently been revealed by Raman spectroscopy that the cellular LD level associates with resistance of CRC cells to erlotinib, which targets EGFR [ 77 ].…”

Progress in therapeutic strategies based on cancer lipid metabolism

“…Furthermore, Penrose et al . demonstrated that LD‐depletion, through the inhibition of lipid synthesis or silencing of PLIN2, significantly attenuated proliferation of colon cancer cells . These studies support LD‐associated proteins as potential targets for cancer treatment.…”