Group X secreted phospholipase A(2) induces lipid droplet formation and prolongs breast cancer cell survival.
BACKGROUND
Alterations in lipid metabolism are inherent to the metabolic transformations that support tumorigenesis. The relationship between the synthesis, storage and use of lipids and their importance in cancer is poorly understood. The human group X secreted phospholipase A2 (hGX sPLA2) releases fatty acids (FAs) from cell membranes and lipoproteins, but its involvement in the regulation of cellular FA metabolism and cancer is not known.


RESULTS
Here we demonstrate that hGX sPLA2 induces lipid droplet (LD) formation in invasive breast cancer cells, stimulates their proliferation and prevents their death on serum deprivation. The effects of hGX sPLA2 are shown to be dependent on its enzymatic activity, are mimicked by oleic acid and include activation of protein kinase B/Akt, a cell survival signaling kinase. The hGX sPLA2-stimulated LD biogenesis is accompanied by AMP-activated protein kinase (AMPK) activation, up-regulation of FA oxidation enzymes and the LD-coating protein perilipin 2, and suppression of lipogenic gene expression. Prolonged activation of AMPK inhibited hGX sPLA2-induced LD formation, while etomoxir, an inhibitor of FA oxidation, abrogated both LD formation and cell survival. The hGX sPLA2-induced changes in lipid metabolism provide a minimal immediate proliferative advantage during growth under optimal conditions, but they confer to the breast cancer cells a sustained ability to resist apoptosis during nutrient and growth factor limitation.


CONCLUSIONS
Our results identify hGX sPLA2 as a novel modulator of lipid metabolism that promotes breast cancer cell growth and survival by stimulating LD formation and FA oxidation.
Department of Molecular and Biomedical Sciences, JoŽef Stefan Institute, Ljubljana, Slovenia. toni.petan@ijs.si.
Anja
A
Pucer
Vesna
V
Brglez
Christine
C
Payré
Jože
J
Pungerčar
Gérard
G
Lambeau
Toni
T
Petan
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival; D016895:Culture Media, Serum-Free; D004789:Enzyme Activation; D004852:Epoxy Compounds / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D054509:Group X Phospholipases A2 / Q000037:antagonists & inhibitors / Q000502:physiology*; D006801:Humans; D006868:Hydrolysis; D050356:Lipid Metabolism / Q000235:genetics*; D009829:Oleic Acids / Q000378:metabolism; D015388:Organelles / Q000201:enzymology; D010084:Oxidation-Reduction; D010713:Phosphatidylcholines / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
D016895:Culture Media, Serum-Free; D004852:Epoxy Compounds; D009829:Oleic Acids; D010713:Phosphatidylcholines; D051057:Proto-Oncogene Proteins c-akt; D055372:AMP-Activated Protein Kinases; C526180:PRKAA1 protein, human; D054509:Group X Phospholipases A2; C054207:etomoxir