The role of membrane fatty acid remodeling in the antitumor mechanism of action of 2-hydroxyoleic acid.
The synthetic fatty acid 2-hydroxyoleic acid (2OHOA) is a potent antitumor drug that we rationally designed to regulate the membrane lipid composition and structure. The lipid modifications caused by 2OHOA treatments induce important signaling changes that end up with cell death (Terés et al., 2012 [1]). One of these regulatory effects is restoration of sphingomyelin levels, which are markedly lower in cancer cells compared to normal cells (Barceló-Coblijn et al., 2011 [2]). In this study, we report another important regulatory effect of 2OHOA on cancer cell membrane composition: a large increase in 2OHOA levels, accounting for ~15% of the fatty acids present in membrane phospholipids, in human glioma (SF767 and U118) and lung cancer (A549) cells. Concomitantly, we observed marked reductions in oleic acid levels and inhibition of stearoyl-CoA desaturase. The impact of these changes on the biophysical properties of the lipid bilayer was evaluated in liposomes reconstituted from cancer cell membrane lipid extracts. Thus, 2OHOA increased the packing of ordered domains and decreased the global order of the membrane. The present results further support and extend the knowledge about the mechanism of action for 2OHOA, based on the regulation of the membrane lipid composition and structure and subsequent modulation of membrane protein-associated signaling.
Department of Biology, University of the Balearic Islands, Balearic Islands, Spain.
Maria Laura
ML
Martin
Gwendolyn
G
Barceló-Coblijn
Rodrigo F M
RF
de Almeida
Maria Antònia
MA
Noguera-Salvà
Silvia
S
Terés
Mónica
M
Higuera
Gerhard
G
Liebisch
Gerd
G
Schmitz
Xavier
X
Busquets
Pablo V
PV
Escribá
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D055592:Biophysical Phenomena; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D002855:Chromatography, Thin Layer; D005227:Fatty Acids / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D013058:Mass Spectrometry; D008563:Membrane Lipids / Q000737:chemistry / Q000378:metabolism; D009369:Neoplasms / Q000737:chemistry / Q000188:drug therapy / Q000378:metabolism; D009829:Oleic Acids / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D010713:Phosphatidylcholines / Q000737:chemistry / Q000378:metabolism; D010714:Phosphatidylethanolamines / Q000737:chemistry / Q000378:metabolism; D010743:Phospholipids / Q000737:chemistry / Q000378:metabolism; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors; D014280:Triglycerides / Q000737:chemistry / Q000378:metabolism
C483229:2-hydroxyoleic acid; D000970:Antineoplastic Agents; D005227:Fatty Acids; D008051:Lipid Bilayers; D008563:Membrane Lipids; D009829:Oleic Acids; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D010743:Phospholipids; D014280:Triglycerides; C483858:phosphatidylethanolamine; C523776:SCD1 protein, human; D013230:Stearoyl-CoA Desaturase