The anti-tumor drug 2-hydroxyoleic acid (Minerval) stimulates signaling and retrograde transport
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Maria L. Torgersen1, Tove Irene Klokk1, Simona Kavaliauskiene1,2, Christian Klose3, Kai Simons3, Tore Skotland1, Kirsten Sandvig1,2
1Department of Molecular Cell Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Norway, and Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Norway
2Department of Molecular Biosciences, University of Oslo, Norway
3Lipotype GmbH, Dresden, Germany
Maria L. Torgersen, email: [email protected]
Keywords: hydroxyoleic acid, minerval, membrane lipid therapy, EGFR, ricin
Received: June 20, 2016 Accepted: October 17, 2016 Published: November 22, 2016
2-hydroxyoleic acid (OHOA, Minerval®) is an example of a substance used for membrane lipid therapy, where the cellular membranes rather than specific proteins constitute the therapeutical target. OHOA is thought to mediate its anti-tumor effect by affecting the biophysical properties of membranes, which leads to altered recruitment and activation of amphitropic proteins, altered cellular signaling, and eventual cell death. Little is known about the initial signaling events upon treatment with OHOA, and whether the altered membrane properties would have any impact on the dynamic intracellular transport system. In the present study we demonstrate that treatment with OHOA led to a rapid release of intracellular calcium and activation of multiple signaling pathways in HeLa cells, including the PI3K-AKT1-MTOR pathway and several MAP kinases, in a process independent of the EGFR. By lipidomics we confirmed that OHOA was incorporated into several lipid classes. Concomitantly, OHOA potently increased retrograde transport of the plant toxin ricin from endosomes to the Golgi and further to the endoplasmic reticulum. The OHOA-stimulated ricin transport seemed to require several amphitropic proteins, including Src, phospholipase C, protein kinase C, and also Ca2+/calmodulin. Interestingly, OHOA induced a slight increase in endosomal localization of the retromer component VPS35. Thus, our data show that addition of a lipid known to alter membrane properties not only affects signaling, but also intracellular transport.
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