title: Involvement of de novo synthesized palmitate and mitochondrial EGFR in EGF induced mitochondrial fusion of cancer cells.
abstract: Increased expressions of fatty acid synthase (FASN) and epidermal growth factor receptor (EGFR) are common in cancer cells. De novo synthesis of palmitate by FASN is critical for the survival of cancer cells via mechanisms independent of its role as an energy substrate. Besides the plasma membrane and the nucleus, EGFR can also localize at the mitochondria; however, signals that can activate mitochondrial EGFR (mtEGFR) and the functions of mtEGFR of cancer cells remain unknown. The present study characterizes mtEGFR in the mitochondria of cancer cells (prostate and breast) and reveals that mtEGFR can promote mitochondrial fusion through increasing the protein levels of fusion proteins PHB2 and OPA1. Activation of plasma membranous EGFR (pmEGFR) stimulates the de novo synthesis of palmitate through activation of FASN and ATP-citrate lyase (ACLy). In vitro kinase assay with isolated mitochondria shows that palmitate can activate mtEGFR. Inhibition of FASN blocks the mtEGFR phosphorylation and palmitoylation induced by EGF. Mutational studies show that the cysteine 797 is important for mtEGFR activation and palmitoylation. Inhibition of FASN can block EGF induced mitochondrial fusion and increased the sensitivity of prostate cancer cells to EGFR tyrosine kinase inhibitor. In conclusion, these results suggest that mtEGFR can be activated by pmEGFR through de novo synthesized palmitate to promote mitochondrial fusion and survival of cancer cells. This mechanism may serve as a novel target to improve EGFR-based cancer therapy.
authors.affiliation: a Department of Biology and Biochemistry; College of Natural Sciences and Mathematics; University of Houston; Houston, TX USA.
authors.forename: Lakshmi Reddy
authors.initials: LR
authors.lastname: Bollu
authors.forename: Jiangong
authors.initials: J
authors.lastname: Ren
authors.forename: Alicia Marie
authors.initials: AM
authors.lastname: Blessing
authors.forename: Rajasekhara Reddy
authors.initials: RR
authors.lastname: Katreddy
authors.forename: Guang
authors.initials: G
authors.lastname: Gao
authors.forename: Lei
authors.initials: L
authors.lastname: Xu
authors.forename: Jinrong
authors.initials: J
authors.lastname: Wang
authors.forename: Fei
authors.initials: F
authors.lastname: Su
authors.forename: Zhang
authors.initials: Z
authors.lastname: Weihua
mesh_terms: D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D003545:Cysteine / Q000378:metabolism; D004351:Drug Resistance / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D054890:Fatty Acid Synthase, Type I / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D063154:Mitochondrial Dynamics / Q000187:drug effects*; D024101:Mitochondrial Proteins / Q000378:metabolism; D010168:Palmitates / Q000378:metabolism*; D000091402:Prohibitins; D011471:Prostatic Neoplasms / Q000473:pathology*; D040081:Protein Array Analysis / Q000379:methods; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism
chemical_list: D024101:Mitochondrial Proteins; C000717331:PHB2 protein, human; D010168:Palmitates; D000091402:Prohibitins; D047428:Protein Kinase Inhibitors; D004815:Epidermal Growth Factor; C518729:FASN protein, human; D054890:Fatty Acid Synthase, Type I; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D003545:Cysteine
keywords: EGFR; cancer; fatty acids synthase; mitochondria; mitochondrial fission; mitochondrial fusion