The triacylglycerol, hydroxytriolein, inhibits triple negative mammary breast cancer cell proliferation through a mechanism dependent on dihydroceramide and Akt

// Francisca Guardiola-Serrano 1 , * , Roberto Beteta-Gobel 1 , * , Raquel Rodriguez-Lorca 1 , Maitane Ibarguren 1 , David J. Lopez 1 , Silvia Teres 1 , Maria Alonso-Sande 1 , Monica Higuera 1 , Manuel Torres 1 , Xavier Busquets 1 and Pablo V. Escriba 1 1 Laboratory of Molecular Cell Biomedicine, Department of Biology, University of the Balearic Islands, E-07122 Palma, Balearic Islands, Spain * These authors contributed equally to this work Correspondence to: Pablo V. Escriba, email: pablo.escriba@uib.es Francisca Guardiola-Serrano, email: francisca.guardiola@uib.es Keywords: hydroxytriolein; membrane lipidtherapy; lipid composition and cancer treatment; autophagy; triple negative breast cancerReceived: January 29, 2019     Accepted: March 04, 2019     Published: April 02, 2019 ABSTRACT The plasma membrane is an attractive target for new anticancer drugs, not least because regulating its lipid structure can control multiple signaling pathways involved in cancer cell proliferation, differentiation and survival. Accordingly, the novel anticancer drug hydroxytriolein (HTO) was designed to interact with and regulate the composition and structure of the membrane, which in turn controls the interaction of amphitropic signaling membrane proteins with the lipid bilayer. Changes in signaling provoked by HTO impair the growth of triple negative breast cancer(TNBC) cells, aggressive breast tumor cells that have a worse prognosis than other types of breast cancers and for which there is as yet no effective targeted therapy. HTO alters the lipid composition and structure of cancer cell membranes, inhibiting the growth of MDA-MB-231 and BT-549 TNBC cells in vitro . Depending on the cellular context, HTO could regulate two pathways involved in TNBC cell proliferation. On the one hand, HTO might stimulate ERK signaling and induce TNBC cell autophagy, while on the other, it could increase dihydroceramide and ceramide production, which would inhibit Akt independently of EGFR activation and provoke cell death. In vivo studies using a model of human TNBC show that HTO and its fatty acid constituent (2-hydroxyoleic acid) impair tumor growth, with no undesired side effects. For these reasons, HTO appears to be a promising anticancer molecule that targets the lipid bilayer ( membrane-lipidtherapy). By regulating membrane lipids, HTO controls important signaling pathways involved in cancer cell growth, the basis of its pharmacological efficacy and safety.