title: Glycerophospholipid profile in oncogene-induced senescence.
abstract: Alterations in lipid metabolism and in the lipid composition of cellular membranes are linked to the pathology of numerous diseases including cancer. However, the influence of oncogene expression on cellular lipid profile is currently unknown. In this work we analyzed changes in lipid profiles that are induced in the course of ERBB2-expression mediated premature senescence. As a model system we used MCF-7 breast cancer cells with doxycycline-inducible expression of NeuT, an oncogenic ERBB2 variant. Affymetrix gene array data showed NeuT-induced alterations in the transcription of many enzymes involved in lipid metabolism, several of which (ACSL3, CHPT1, PLD1, LIPG, MGLL, LDL and NPC1) could be confirmed by quantitative realtime PCR. A study of the glycerophospholipid and lyso-glycerophospholipid profiles, obtained by high performance liquid chromatography coupled to Fourier-transform ion cyclotron resonance-mass spectrometry revealed senescence-associated changes in numerous lipid species, including mitochondrial lipids. The most prominent changes were found in PG(34:1), PG(36:1) (increased) and LPE(18:1), PG(40:7) and PI(36:1) (decreased). Statistical analysis revealed a general trend towards shortened phospholipid acyl chains in senescence and a significant trend to more saturated acyl chains in the class of phosphatidylglycerol. Additionally, the cellular cholesterol content was elevated and accumulated in vacuoles in senescent cells. These changes were accompanied by increased membrane fluidity. In mitochondria, loss of membrane potential along with altered intracellular distribution was observed. In conclusion, we present a comprehensive overview of altered cholesterol and glycerophospholipid patterns in senescence, showing that predominantly mitochondrial lipids are affected and lipid species less susceptible to peroxidation are increased.
authors.affiliation: Leibniz Research Centre for Working Environment and Human Factors, TU Dortmund University, Dortmund, Germany. cadenas@ifado.de
authors.forename: Cristina
authors.initials: C
authors.lastname: Cadenas
authors.forename: Sonja
authors.initials: S
authors.lastname: Vosbeck
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Hein
authors.forename: Birte
authors.initials: B
authors.lastname: Hellwig
authors.forename: Alice
authors.initials: A
authors.lastname: Langer
authors.forename: Heiko
authors.initials: H
authors.lastname: Hayen
authors.forename: Dennis
authors.initials: D
authors.lastname: Franckenstein
authors.forename: Bettina
authors.initials: B
authors.lastname: Büttner
authors.forename: Seddik
authors.initials: S
authors.lastname: Hammad
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Marchan
authors.forename: Matthias
authors.initials: M
authors.lastname: Hermes
authors.forename: Silvia
authors.initials: S
authors.lastname: Selinski
authors.forename: Jörg
authors.initials: J
authors.lastname: Rahnenführer
authors.forename: Begüm
authors.initials: B
authors.lastname: Peksel
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Török
authors.forename: László
authors.initials: L
authors.lastname: Vígh
authors.forename: Jan G
authors.initials: JG
authors.lastname: Hengstler
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D005260:Female; D018734:Genes, erbB-2; D020404:Glycerophospholipids / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D050356:Lipid Metabolism; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D014617:Vacuoles / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D020404:Glycerophospholipids; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human