Normalization of sphingomyelin levels by 2-hydroxyoleic acid induces autophagic cell death of SF767 cancer cells.
The very high mortality rate of gliomas reflects the unmet therapeutic need associated with this type of brain tumor. We have discovered that the plasma membrane fulfills a critical role in the propagation of tumorigenic signals, whereby changes in membrane lipid content can either activate or silence relevant pathways. We have designed a synthetic fatty acid, 2-hydroxyoleic acid (2OHOA), that specifically activates sphingomyelin synthase (SGMS), thereby modifying the lipid content of cancer cell membranes and restoring lipid levels to those found in normal cells. In reverting, the structure of the membrane by activating SGMS, 2OHOA inhibits the RAS-MAPK pathway, which in turn fails to activate the CCND (Cyclin D)-CDK4/CDK6 and PI3K-AKT1 pathways. The overall result in SF767 cancer cells, a line that is resistant to apoptosis, is the sequential induction of cell cycle arrest, cell differentiation and autophagy. Such effects are not observed in normal cells (MRC-5) and thus, this specific activation of programmed cell death infers greater efficacy and lower toxicity to 2OHOA than that associated with temozolomide (TMZ), the reference drug for the treatment of glioma.
Molecular Cell Biomedicine, Department of Biology-IUNICS, University of the Balearic Islands, Palma de Mallorca, Spain.
Silvia
S
Terés
Victoria
V
Lladó
Mónica
M
Higuera
Gwendolyn
G
Barceló-Coblijn
M Laura
ML
Martin
Maria Antònia
MA
Noguera-Salvà
Amaia
A
Marcilla-Etxenike
José Manuel
JM
García-Verdugo
Mario
M
Soriano-Navarro
Carlos
C
Saus
Ulises
U
Gómez-Pinedo
Xavier
X
Busquets
Pablo V
PV
Escribá
D001343:Autophagy / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005910:Glioma / Q000473:pathology*; D006801:Humans; D008954:Models, Biological; D009829:Oleic Acids / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013109:Sphingomyelins / Q000378:metabolism*
C483229:2-hydroxyoleic acid; D009829:Oleic Acids; D013109:Sphingomyelins