title: 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.
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave SL-79, New Orleans, LA 70112, USA.
authors.forename: Harrison
authors.initials: H
authors.lastname: Penrose
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave SL-79, New Orleans, LA 70112, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Heller
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave SL-79, New Orleans, LA 70112, USA.
authors.forename: Chloe
authors.initials: C
authors.lastname: Cable
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave SL-79, New Orleans, LA 70112, USA; Pathology Department, Assiut University, Assiut, Egypt.
authors.forename: Rania
authors.initials: R
authors.lastname: Makboul
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave SL-79, New Orleans, LA 70112, USA.
authors.forename: Gita
authors.initials: G
authors.lastname: Chadalawada
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave SL-79, New Orleans, LA 70112, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Pathology, Saint Louis University School of Medicine, 1402 South Grand Blvd, Saint Louis, MO 63104, USA.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Crawford
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave SL-79, New Orleans, LA 70112, USA. Electronic address: ssavkovi@tulane.edu.
authors.forename: Suzana D
authors.initials: SD
authors.lastname: Savkovic
mesh_terms: D002452:Cell Count; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D066246:ErbB Receptors / Q000378:metabolism*; D025461:Feedback, Physiological; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D019073:HT29 Cells; D006801:Humans; D066292:Lipid Droplets / Q000378:metabolism*; D050356:Lipid Metabolism; D037761:Sirtuins / Q000378:metabolism*
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C512478:EGFR protein, human; D066246:ErbB Receptors; C516592:SIRT6 protein, human; D037761:Sirtuins
keywords: Colon cancer; EGFR; FOXO3; Lipid droplet; SIRT6