Normalization of sphingomyelin levels by 2-hydroxyoleic acid induces autophagic cell death of SF767 cancer cells
Volume 8, Issue 10
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Pages 1542 - 1544http://dx.doi.org/10.4161/auto.21341
: cancer, cell membrane, lipid bilayer and proliferation, minerval, phospholipid, signaling
Authors: Silvia Terés, Victoria Lladó, Mónica Higuera, Gwendolyn Barceló-Coblijn, M. Laura Martin, Maria Antònia Noguera-Salvà, Amaia Marcilla-Etxenike, José Manuel García-Verdugo, Mario Soriano-Navarro, Carlos Saus, Ulises Gómez-Pinedo, Xavier Busquets and Pablo V. Escribá View affiliations
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.
Autophagic Punctum to:
S Terés, V Lladó, M Higuera, G Barceló-Coblijn, ML Martin, MA Noguera-Salvà, et al. 2-Hydroxyoleate, a nontoxic membrane binding anticancer drug, induces glioma cell differentiation and autophagy. Proc Natl Acad Sci U S A 2012; 109: 8489-94
PMID: 22586083 DOI: 10.1073/pnas.1118349109
Received: July 2, 2012; Accepted: July 3, 2012; Published Online: August 15, 2012
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