title: De novo lipogenesis protects cancer cells from free radicals and chemotherapeutics by promoting membrane lipid saturation.
abstract: Activation of de novo lipogenesis in cancer cells is increasingly recognized as a hallmark of aggressive cancers and has been implicated in the production of membranes for rapid cell proliferation. In the current report, we provide evidence that this activation has a more profound role. Using a mass spectrometry-based phospholipid analysis approach, we show that clinical tumor tissues that display the lipogenic phenotype show an increase in the degree of lipid saturation compared with nonlipogenic tumors. Reversal of the lipogenic switch in cancer cells by treatment with the lipogenesis inhibitor soraphen A or by targeting lipogenic enzymes with small interfering RNA leads to a marked decrease in saturated and mono-unsaturated phospholipid species and increases the relative degree of polyunsaturation. Because polyunsaturated acyl chains are more susceptible to peroxidation, inhibition of lipogenesis increases the levels of peroxidation end products and renders cells more susceptible to oxidative stress-induced cell death. As saturated lipids pack more densely, modulation of lipogenesis also alters lateral and transversal membrane dynamics as revealed by diffusion of membrane-targeted green fluorescent protein and by the uptake and response to doxorubicin. These data show that shifting lipid acquisition from lipid uptake toward de novo lipogenesis dramatically changes membrane properties and protects cells from both endogenous and exogenous insults. These findings provide important new insights into the role of de novo lipogenesis in cancer cells, and they provide a rationale for the use of lipogenesis inhibitors as antineoplastic agents and as chemotherapeutic sensitizers.
authors.affiliation: Laboratory for Experimental Medicine and Endocrinology, K.U. Leuven, Leuven, Belgium.
authors.forename: Evelien
authors.initials: E
authors.lastname: Rysman
authors.forename: Koen
authors.initials: K
authors.lastname: Brusselmans
authors.forename: Katryn
authors.initials: K
authors.lastname: Scheys
authors.forename: Leen
authors.initials: L
authors.lastname: Timmermans
authors.forename: Rita
authors.initials: R
authors.lastname: Derua
authors.forename: Sebastian
authors.initials: S
authors.lastname: Munck
authors.forename: Paul P
authors.initials: PP
authors.lastname: Van Veldhoven
authors.forename: David
authors.initials: D
authors.lastname: Waltregny
authors.forename: Veerle W
authors.initials: VW
authors.lastname: Daniëls
authors.forename: Jelle
authors.initials: J
authors.lastname: Machiels
authors.forename: Frank
authors.initials: F
authors.lastname: Vanderhoydonc
authors.forename: Karine
authors.initials: K
authors.lastname: Smans
authors.forename: Etienne
authors.initials: E
authors.lastname: Waelkens
authors.forename: Guido
authors.initials: G
authors.lastname: Verhoeven
authors.forename: Johannes V
authors.initials: JV
authors.lastname: Swinnen
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000378:metabolism; D002455:Cell Division; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D002784:Cholesterol / Q000378:metabolism; D004317:Doxorubicin / Q000378:metabolism; D005609:Free Radicals / Q000494:pharmacology*; D045325:HCT116 Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D015227:Lipid Peroxidation; D050155:Lipogenesis / Q000502:physiology*; D008297:Male; D008563:Membrane Lipids / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D010743:Phospholipids / Q000378:metabolism; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics; D021241:Spectrometry, Mass, Electrospray Ionization; D014162:Transfection; D014280:Triglycerides / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D005609:Free Radicals; D008563:Membrane Lipids; D010743:Phospholipids; D034741:RNA, Small Interfering; D014280:Triglycerides; D004317:Doxorubicin; D002784:Cholesterol