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

Silvia Terés

Molecular Cell Biomedicine; Department of Biology-IUNICS; University of the Balearic Islands; Palma de Mallorca, Spain

Victoria Lladó

Molecular Cell Biomedicine; Department of Biology-IUNICS; University of the Balearic Islands; Palma de Mallorca, Spain

Mónica Higuera

Molecular Cell Biomedicine; Department of Biology-IUNICS; University of the Balearic Islands; Palma de Mallorca, Spain

Gwendolyn Barceló-Coblijn

Molecular Cell Biomedicine; Department of Biology-IUNICS; University of the Balearic Islands; Palma de Mallorca, Spain

M. Laura Martin

Molecular Cell Biomedicine; Department of Biology-IUNICS; University of the Balearic Islands; Palma de Mallorca, Spain

Maria Antònia Noguera-Salvà

Molecular Cell Biomedicine; Department of Biology-IUNICS; University of the Balearic Islands; Palma de Mallorca, Spain

Amaia Marcilla-Etxenike

Molecular Cell Biomedicine; Department of Biology-IUNICS; University of the Balearic Islands; Palma de Mallorca, Spain

José Manuel García-Verdugo

Laboratorio de Morfología Celular; Unidad Mixta CIPF-UVEG; CIBERNED; Valencia, Spain

Mario Soriano-Navarro

Laboratorio de Morfología Celular; Unidad Mixta CIPF-UVEG; CIBERNED; Valencia, Spain

Carlos Saus

Molecular Cell Biomedicine; Department of Biology-IUNICS; University of the Balearic Islands; Palma de Mallorca, Spain

Ulises Gómez-Pinedo

Laboratory of Regenerative Medicine; Neuroscience Institute; Hospital Clínico San Carlos; Madrid, Spain

Xavier Busquets

Molecular Cell Biomedicine; Department of Biology-IUNICS; University of the Balearic Islands; Palma de Mallorca, Spain

Pablo V. Escribá

Corresponding author: pablo.escriba@uib.es
Molecular Cell Biomedicine; Department of Biology-IUNICS; University of the Balearic Islands; Palma de Mallorca, Spain

Abstract:
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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