Differential effect of 2-hydroxyoleic acid enantiomers on protein (sphingomyelin synthase) and lipid (membrane) targets

Piotto, Stefano; Bianchino, Erminia; Guardiola-Serrano, Francisca; Funari, Sérgio S.; Busquets, Xavier; Ibarguren, Maitane; Iannelli, Pio; Concilio, Simona; Alonso-Sande, María; López, David J.; Escribá, Pablo V.; Barceló-Coblijn, Gwendolyn; Martin, Maria Laura; Terés, Silvia

doi:10.1016/j.bbamem.2013.12.023

Journal Article

PUBDB-2014-04165

Differential effect of 2-hydroxyoleic acid enantiomers on protein (sphingomyelin synthase) and lipid (membrane) targets

Piotto, S. (Corresponding Author) ; Concilio, S. ; Bianchino, E. ; Iannelli, P. ; López, D. J. ; Terés, S. ; Ibarguren, M. ; Barceló-Coblijn, G. ; Martin, M. L. ; Guardiola-Serrano, F. ; Alonso-Sande, M. ; Funari, S. S. ; Busquets, X. ; Escribá, P. V.Extern*

2014
Elsevier Amsterdam

Biochimica et biophysica acta / Biomembranes 1838(6), 1628 - 1637 (2014) [10.1016/j.bbamem.2013.12.023] special issue: "Membrane Structure and Function: Relevance in the Cell's Physiology, Pathology and Therapy"

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Please use a persistent id in citations: doi:10.1016/j.bbamem.2013.12.023

Abstract: The complex dual mechanism of action of 2-hydroxyoleic acid (2OHOA), a potent anti-tumor compound used in membrane lipid therapy (MLT), has yet to be fully elucidated. It has been demonstrated that 2OHOA increases the sphingomyelin (SM) cell content via SM synthase (SGMS) activation. Its presence in membranes provokes changes in the membrane lipid structure that induce the translocation of PKC to the membrane and the subsequent overexpression of CDK inhibitor proteins (e.g., p21(Cip1)). In addition, 2OHOA also induces the translocation of Ras to the cytoplasm, provoking the silencing of MAPK and its related pathways. These two differential modes of action are triggered by the interactions of 2OHOA with either lipids or proteins. To investigate the molecular basis of the different interactions of 2OHOA with membrane lipids and proteins, we synthesized the R and S enantiomers of this compound. A molecular dynamics study indicated that both enantiomers interact similarly with lipid bilayers, which was further confirmed by X-ray diffraction studies. By contrast, only the S enantiomer was able to activate SMS in human glioma U118 cells. Moreover, the anti-tumor efficacy of the S enantiomer was greater than that of the R enantiomer, as the former can act through both MLT mechanisms. The present study provides additional information on this novel therapeutic approach and on the magnitude of the therapeutic effects of type-1 and type-2 MLT approaches. This article is part of a Special Issue entitled: Membrane Structure and Function: Relevance in the Cell's Physiology, Pathology and Therapy.

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