The Novel Anticancer Drug Hydroxytriolein Inhibits Lung Cancer Cell Proliferation via a Protein Kinase C<i>α</i>– and Extracellular Signal-Regulated Kinase 1/2–Dependent Mechanism

Guardiola-Serrano, Francisca; Beteta-Göbel, Roberto; Rodríguez-Lorca, Raquel; Ibarguren, Maitane; López, David J.; Terés, Silvia; Álvarez, Rafael; Alonso-Sande, M.; Busquets, Xavier; Escribá, Pablo V.

doi:10.1124/jpet.114.222281

Cited by 14 publications

(22 citation statements)

References 50 publications

(65 reference statements)

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“…Exposing TNBC cells to HTO or TO (prepared as described previously [30]) reduced the number of viable cells in culture in a dose- and time-dependent manner. After 48 h, HTO more strongly affected BT-549 and Hs-5748T cells than TO (IC 50 59.2 ± 4.4 μM and 297 ± 73 μM for HTO; 146.6 ± 5 μM vs 412.5 ± 78 μM for TO, respectively: Figure 1A).…”

Section: Resultsmentioning

confidence: 99%

“…We recently showed that a more stable TO analogue, hydroxytriolein (HTO), has a stronger antitumor efficacy than TO against non-small cell lung cancer (NSCLC). HTO is a 2-hydroxy fatty-acyl TO derivative that regulates membrane lipid structure, favoring the membrane translocation and activation of PKC and ERK, as well as the production of reactive oxygen species (ROS) and macroautophagy specifically in cancer but not in normal cells [30]. Here, we have used different human TNBC cell lines to evaluate the antitumor potential of HTO.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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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-lipid therapy). By regulating membrane lipids, HTO controls important signaling pathways involved in cancer cell growth, the basis of its pharmacological efficacy and safety.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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“…in terms of the glycerol backbone and three fatty acids. These molecules are good candidates for treating APBD and other conditions through membrane lipid therapy, particularly because they modulate the composition and structure of cell membranes, and because they are more stable than nonhydroxylated triacylglycerols (36). This therapeutic approach involves the regulation of the membrane lipid structure, as has formerly been considered to treat other CNS conditions like Alzheimer's disease or gliomas (37,38).…”

Section: Discussionmentioning

confidence: 99%

“…This metabolism could reduce the bioavailability of TH and its therapeutic effects in patients. In order to overcome this problem, we designed a more stable hydroxylated TH analog (TGM0), a modification that offers some protection from triacylglycerol metabolism by lipases (36). TGM0 significantly increased GBE1Y329S activity in PBMC cells from APBD patients homozygous for that mutation and TGM5 also enhanced GBE1Y329S activity in vitro and ex vivo (Fig.…”

Section: Discussionmentioning

confidence: 99%

Triacylglycerol mimetics regulate membrane interactions of glycogen branching enzyme: implications for therapy

Álvarez

Casas

López

et al. 2017

Journal of Lipid Research

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Adult polyglucosan body disease (APBD) is a neurological disorder characterized by adult-onset neurogenic bladder, spasticity, weakness, and sensory loss. The disease is caused by aberrant glycogen branching enzyme (GBE) (GBE1Y329S) yielding less branched, globular, and soluble glycogen, which tends to aggregate. We explore here whether, despite being a soluble enzyme, GBE1 activity is regulated by protein-membrane interactions. Because soluble proteins can contact a wide variety of cell membranes, we investigated the interactions of purified WT and GBE1Y329S proteins with different types of model membranes (liposomes). Interestingly, both triheptanoin and some triacylglycerol mimetics (TGMs) we have designed (TGM0 and TGM5) markedly enhance GBE1Y329S activity, possibly enough for reversing APBD symptoms. We show that the GBE1Y329S mutation exposes a hydrophobic amino acid stretch, which can either stabilize and enhance or alternatively, reduce the enzyme activity via alteration of protein-membrane interactions. Additionally, we found that WT, but not Y329S, GBE1 activity is modulated by Ca and phosphatidylserine, probably associated with GBE1-mediated regulation of energy consumption and storage. The thermal stabilization and increase in GBE1Y329S activity induced by TGM5 and its omega-3 oil structure suggest that this molecule has a considerable therapeutic potential for treating APBD.

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“…Altering this membrane lipid switch (i.e., changing the membrane lipid composition) may affect the localization and activity of proteins that promote proliferation, such as the farnesylated small GTPase Ras [251,252], and it also regulates membrane anchoring of tumor suppressors like PKC. Certain synthetic lipids like 2OHOA [88] and hydroxytriolein [249,253] alter the membrane's composition, reversing cancer cell proliferation and preventing the uncontrolled growth of cancer cells by relocating Ras to the cytosol [21], FoxO1 to the nucleus, PKC to the plasma membrane [21,98,245], or PKC to the cytosol through hydroxytriolein activity [253]. These alterations attenuate cancer cell proliferation, and induce differentiation, ER stress and ERK-dependent autophagic cell death.…”

Section: Protein-lipid Interactions and Cell Switchesmentioning

confidence: 99%

The Implications for Cells of the Lipid Switches Driven by Protein–Membrane Interactions and the Development of Membrane Lipid Therapy

Torres

Rosselló

Fernández‐García

et al. 2020

IJMS

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The cell membrane contains a variety of receptors that interact with signaling molecules. However, agonist–receptor interactions not always activate a signaling cascade. Amphitropic membrane proteins are required for signal propagation upon ligand-induced receptor activation. These proteins localize to the plasma membrane or internal compartments; however, they are only activated by ligand-receptor complexes when both come into physical contact in membranes. These interactions enable signal propagation. Thus, signals may not propagate into the cell if peripheral proteins do not co-localize with receptors even in the presence of messengers. As the translocation of an amphitropic protein greatly depends on the membrane’s lipid composition, regulation of the lipid bilayer emerges as a novel therapeutic strategy. Some of the signals controlled by proteins non-permanently bound to membranes produce dramatic changes in the cell’s physiology. Indeed, changes in membrane lipids induce translocation of dozens of peripheral signaling proteins from or to the plasma membrane, which controls how cells behave. We called these changes “lipid switches”, as they alter the cell’s status (e.g., proliferation, differentiation, death, etc.) in response to the modulation of membrane lipids. Indeed, this discovery enables therapeutic interventions that modify the bilayer’s lipids, an approach known as membrane-lipid therapy (MLT) or melitherapy.

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The Novel Anticancer Drug Hydroxytriolein Inhibits Lung Cancer Cell Proliferation via a Protein Kinase Cα– and Extracellular Signal-Regulated Kinase 1/2–Dependent Mechanism

Cited by 14 publications

References 50 publications

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

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

Triacylglycerol mimetics regulate membrane interactions of glycogen branching enzyme: implications for therapy

The Implications for Cells of the Lipid Switches Driven by Protein–Membrane Interactions and the Development of Membrane Lipid Therapy

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