The anti-tumor drug 2-hydroxyoleic acid (Minerval) stimulates signaling and retrograde transport

Abstract

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.

The role of lipid species in membranes and cancer-related changes

“…The modified fatty acid 2-hydroxyoleic acid was introduced as an agent that should activate SM synthase and thus change biophysical properties of the membrane, leading to altered cell signaling in cancer cells and eventually to cell death [150,151]. When we tested this substance on HeLa cells we did not observe any major changes in the lipidome, and no differences were observed for SM species in control cells or cells incubated with oleic acid or 2-hydroxyoleic acid [152]. We did, however, after treatment with 2-hydroxyoleic acid observe a reduced membrane fluidity, a rapid release of intracellular calcium, activation of several signaling pathways and a large increase in retrograde transport of the plant toxin ricin to the Golgi apparatus and the endoplasmic reticulum.…”

Protein–lipid complexes: molecular structure, current scenarios and mechanisms of cytotoxicity

“…145,146 Minerval® is considered a potent therapeutic agent for targeting the cellular membrane and is supposed to accomplish its tumoricidal action by modifying the biophysical features of lipid bilayers, leading to activation and modication of cellular signaling and amphitropic proteins and nally causing cell death. 147 Therefore, it appears reasonable to suggest preparation of new protein-lipid complexes with Min-erval® and investigation of their tumoricidal and other biological effects. Finally, there are numerous dairy products containing very important proteins present in high concentrations with potent biological roles that can be produced using various simple techniques, such as heat treatment, acid pH, and pressure.…”

Changes in the plasma membrane in metabolic disease: impact of the membrane environment on G protein‐coupled receptor structure and function

“…Changes in expression of lipid metabolism genes have been found to correlate with tumourigenesis and with patient survival in breast, prostate, colorectal, ovarian and brain cancers (Madhavan et al, ; Hirsch et al, ; Hilvo et al, ; Crous‐Bou et al, ). Moreover, agents capable of modifying the altered membrane composition and organization in cancer cells, and consequently, the downstream signalling events are of great therapeutic interest in this group of diseases (Martinez et al, ; Teres et al, ; Escriba et al, ; Torgersen et al, ).…”

“…The investigational drug, Minerval®, a synthetic derivative of 2‐hydroxyoleic acid, is an anti‐tumour agent that has been shown to act specifically on cancer cells by normalizing the abnormal membrane lipid composition that is related to the activation of the proliferative Ras signalling events. Minerval® acts by changing the lipid order, enhancing the order of lipid rafts and up‐regulating sphingomyelin (SM) synthase 1 activity leading to increased membrane SM, which subsequently activates a cascade of signalling effectors responsible for cell cycle arrest and cell death (Martinez et al, ; Teres et al, ; Torgersen et al, ).…”