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The anti-tumor drug 2-hydroxyoleic acid regulates the oncogenic potassium channel Kv10.1



2-hydroxyoleic acid (2OHOA) is a synthetic fatty acid with antitumor properties that alters membrane composition and structure, which in turn influences the functioning of membrane proteins and cell signaling. In this study, we propose a novel antitumoral mechanism of 2OHOA accomplished through the regulation of Kv10.1 channels. We evaluated the effects of 2OHOA on Kv10.1 channels expressed in HEK-293 cells by using electrophysiological techniques and a cell proliferation assay.


2OHOA increased Kv10.1 channel currents in a voltage-dependent manner, shifted its conductance-voltage relationship towards negative potentials, and accelerated its activation kinetics. Moreover, 2OHOA reduced proliferation of cells that exogenously (HEK-293) and endogenously (MCF-7) expressed Kv10.1 channels. It is worth noting that the antiproliferative effect of 2OHOA was maintained in HEK-293 cells expressing a non-conducting mutant of Kv10.1 channel (Kv10.1-F456A), while it did not affect HEK-293 cells not expressing Kv10.1 channels, suggesting that 2OHOA interferes with a non-conducting function of Kv10.1 channels involved in cell proliferation. Finally, we found that 2OHOA can act synergistically with astemizole, a Kv10.1 channel blocker, to decrease cell proliferation more efficiently.


Our data suggest that 2OHOA decreases cell proliferation, at least in part, by regulating Kv10.1 channels.

1 Background

2-hydroxyoleic acid (2OHOA) is a synthetic structural analogue of oleic acid [1]. Insertion of 2OHOA into the plasma membrane alters its structure and biophysical properties [2,3,4], which in turn influences the functioning of membrane proteins and cell signaling [5,6,7,8,9]. In vitro and in vivo studies have shown that 2OHOA displays antitumor properties in different cancer cell lines, but neither toxic nor antiproliferative effects on non-tumor cells [10, 11]. Several mechanisms have been proposed to explain the action of 2OHOA; for example, by modifying the membrane microdomain organization, 2OHOA affects the recruitment and activity of G-proteins, protein kinase C (PKC) and adenylyl cyclases [7, 12, 13]. It has been demonstrated that 2OHOA increases the sphingomyelin content via sphingomyelin synthase activation [8, 10, 14, 15]. Additionally, this drug induces endoplasmic reticulum stress, autophagy, cell cycle arrest, and uncouple oxidative phosphorylation [6, 13, 16,17,18]. Hitherto, it is unknown whether the changes on the plasma membrane properties induced by 2OHOA affect the functioning of transport proteins, like ion channels.

In this scenario, ion channels are transmembrane proteins highly susceptible to alterations of the plasma membrane. Increasing evidence supports the sensitivity of ion channels to the membrane environment [19, 20], whether by specific lipid-protein interactions or by changes in the membrane biophysical properties, but most likely as a mixture of both [21].

KV10.1 is a voltage-gated potassium channel associated to specific membrane microdomains and it is affected by strategies that disturb such domains [22]. This ion channel has been associated with oncogenesis and tumor progression [23, 24]. Remarkably, KV10.1 is ectopically expressed in over 70% of human non-central nervous systems cancers [25,26,27], whereas in healthy tissue is mainly found in the central nervous system [28], but also at low levels in myoblasts, placenta, testis, and adrenal glands [25, 29, 30]. KV10.1 is involved in cell proliferation and survival [31,32,33], angiogenesis [34], and cell migration and invasion [35, 36]. Blocking the potassium flow through KV10.1 channels disrupts the cell cycle progression and induces a significant decrease in cell proliferation and migration [27, 31, 36, 37]; however, is noteworthy that the oncogenic potential of KV10.1 channel is also independent of its ion-conductive activity, as non-conductive mutants still preserve the ability to induce cell proliferation and a transformed phenotype [34, 38].

This study aimed to explore if the plasma membrane targeting drug, 2OHOA, modulates the functioning of KV10.1 channels as part of its mechanisms to regulate cell proliferation.

2 Methods

2.1 Cell culture and compounds

HEK-293 [ATCC® CRL-1573™] and MCF-7 [ATCC® CRL-HTB-22™] cells were cultured in 35 mm culture dishes (Corning, Corning, NY, USA) at 37 °C in a humidified air atmosphere containing 5% CO2. Cells were maintained in DMEM (GIBCO, Grand Island, NY, USA) supplemented with 10% (v/v) fetal bovine serum (Corning Life Sciences, Manassas, VA, USA) and 1% (v/v) antibiotic–antimycotic solution (Sigma-Aldrich, St. Louis, MO, USA). Sodium salt of 2-hidroxioleic acid (2OHOA) and astemizole were purchased from Avanti Polar Lipids (Alabaster, AL, USA) and Sigma-Aldrich, respectively. Stocks of 2OHOA and astemizole were prepared in aqueous solution and dimethyl sulfoxide (DMSO) respectively and diluted to the final desired concentrations.

2.2 Cell transfection

HEK-293 cells were transiently co-transfected with the cDNAs encoding the Kv10.1 channel (kindly provided by Dr. Michael C. Sanguinetti, University of Utah, USA) and the enhanced green fluorescence protein (EGFP), the Kv10.1 (F546A) mutant channel and EGFP (for Fig. 3D) or transfected only with EGFP (for Fig. 3E) using the Lipofectamine 2000 reagent (Invitrogen, Carlsbad, CA, USA) according to manufacturer’s specifications. In all cases the transfection efficiency was of ~ 50–60%. For electrophysiological recordings, cells were used 24 h after transfection.

2.3 Cell proliferation assay

MCF-7, HEK-293 cells and HEK-293 cells expressing Kv10.1 channels were seeded in 96-well plates at different densities (5000–20,000 cells/per well) and cultured overnight. Cells were then treated with 12.5–1000 μM of 2OHOA and/or 5 μM of astemizole for 24 h, 48 h or 72 h before the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenylte-trazolium bromide (MTT) assay. MTT reagent (5 mg/ml in PBS) was then added to each well and incubated for 4 h. Finally, cells were lysed with 10% SDS. A Multiskan™ FC Microplate Photometer (Thermo Fisher Scientific, Waltham, MA, USA) was used to measure the absorbance at 570 nm. The percentage of viable cells after 2OHOA and/or astemizole treatment was calculated by dividing the absorbance of the treated group by that of the control group.

2.4 Electrophysiological recordings

Kv10.1 currents in HEK-293 cells were recorded at room temperature using the whole-cell patch clamp technique with an Axopatch 200B amplifier (Molecular Devices, Sunnyvale, CA, USA) and a Digidata 1440A interface (Molecular Devices) controlled by the pCLAMP 10 software (Molecular Devices). Currents were filtered with a four-pole Bessel filter at 1 kHz and digitized at 10 kHz. The specific voltage-clamp protocols used are described in the Results section. Recording pipettes were pulled with a micropipette programable puller (Sutter Instruments, Novato, CA, USA) and had a resistance of 1.5–2.5 MΩ when filled with the internal solution. The external solution contained (in mM): 140 NaCl, 4 KCl, 1 MgCl2, 10 HEPES, 1.8 CaCl2, and 10 glucose, pH 7.4 (NaOH). The pipette solution contained (in mM): 130 KCl, 5 MgCl2, 10 EGTA, 5K2ATP, and 10 HEPES, pH 7.2 (KOH). Solutions were applied using the Fast-Step Perfusion System VC-77SP (Warner Instruments, Hamden, CT, USA).

2.5 Data analysis and statistics

Patch clamp data were processed using Clampfit 10 (Molecular Devices) and analyzed in Origin 8.6 (OriginLab Corp., Northampton, MA, USA) software. Conductance-voltage (GV) relationships were calculated according to the equation:


where Imax is the maximum current amplitude at the test potential V and VKrev is the potassium reversal potential. The voltage dependence was determined from the GV curves fitted to a Boltzmann equation:


where V is the test potential, V1/2 is the potential at which the conductance was half-activated, and K is the slope.

Data are presented as the mean ± SEM. Statistical comparisons were determined using ANOVA and paired or one-sample Student’s t-test. Statistical significance was set at p < 0.05.

3 Results

3.1 2OHOA increased Kv10.1 currents amplitude in a voltage dependent manner

The effect of 2OHOA on Kv10.1 channels was explored using the whole-cell configuration of the patch clamp technique. A 200 μM concentration of 2OHOA is commonly employed for in vitro studies and was selected for the electrophysiological experiments.

Kv10.1 currents were elicited by 500-ms depolarizing pulses from − 80 mV to + 90 mV (in 10 mV increments) followed by a pulse to − 50 mV, from a holding potential of − 100 mV. Representative Kv10.1 current traces are shown before (Fig. 1A) and after application of 200 μM 2OHOA (Fig. 1A). 2OHOA increased the Kv10.1 current amplitude in the whole voltage range (Fig. 1C), but with a clear voltage dependence (Fig. 1D), showing the higher effect at voltages close to the activation threshold (n = 13). To further characterize the effects of 2OHOA on Kv10.1 channels, we determined the conductance-voltage relationship (GV curve) from untreated (control) and 2OHOA treated cells (Fig. 2A). The conductance-voltage relationship is displaced towards more negative voltages after application of 200 μM 2OHOA, indicating that Kv10.1 channels are more prone to open. The mean activation parameters in untreated and 2OHOA treated cells were V1/2 = 5.9 ± 0.9 mV, k = 21.6 ± 0.8 and V1/2 = − 6.2 ± 1.1 mV, k = 23.6 ± 1.0, respectively (n = 13). Furthermore, we analyzed the effect of 2OHOA on the activation kinetics of Kv10.1 currents like those shown in Fig. 1A, B. A monoexponential function was fitted to the activation recording data. 2OHOA significantly accelerated the activation rate in the range of − 20 to 60 mV (Fig. 2B, n = 9). Finally, we explored if the Cole-More shift, a characteristic of Kv10.1 channels which reflect a slowing of current activation kinetics by hyperpolarizing pulses, is affected by 2OHOA. We evaluated this phenomenon by applying prepulses to hyperpolarized potentials from − 130 to − 70 mV (in 10 mV increments), followed by a depolarizing pulse to + 60 mV to open the channels. In drug-free conditions, Kv10.1 currents displayed their characteristic behavior, activating more slowly as the prepulse potential become more negative (Fig. 2C). Notably, although 2OHOA accelerated the current activation, kinetics remained dependent on the prepulse potential, i.e., the Cole-More shift was not affected (Fig. 2D).

Fig. 1
figure 1

2OHOA increases Kv10.1 currents in a voltage-dependent manner. A, B Representative recordings of Kv10.1 currents before (A) and after application of 200 µM 2OHOA (B), from the same cell. Currents were evoked by 500 ms depolarizing steps to test potentials ranging from -80 to + 90 mV in 10 mV increments from a holding potential of -100 mV. C normalized I-V relationships for currents measured at the end of the 500 ms pulses before (squares) and after 2OHOA (circles). D Kv10.1 current increase by 2OHOA plotted as a function of the test potential. Data are represented as mean ± SEM (n = 13 cells)

Fig. 2
figure 2

Effect of 2OHOA on the voltage-dependence of activation, activation kinetics and Cole-More shift of Kv10.1 channel. A conductance-voltage (GV) curves before (squares) and after application of 200 µM 2OHOA (circles). The V1/2 values were 5.9 ± 0.9 mV and − 6.2 ± 1.1 mV for currents recorded before and after 2OHOA, respectively (n = 13 cells). B time constant of activation kinetics as a function of test potential before (squares) and after 2OHOA application (circles; n = 9 cells). C, D Representative Kv10.1 currents at + 60 mV evoked with the protocol shown inset in control (C) and 200 µM 2OHOA treated cells (D). similar results were obtained in five more cells. Data are represented as mean ± SEM. *p < 0.05, **p < 0.01, NS: Not significant

3.2 2OHOA inhibited cell proliferation in Kv10.1 expressing cells

We used the MTT assay to determine whether proliferation of Kv10.1 expressing cells was altered by 2OHOA. In addition, we used astemizole, a well-known pore blocker of Kv10.1 channels that decreases cell proliferation by its action on this channel [39]. Initially, HEK-293 cells expressing Kv10.1 channels were treated with 2OHOA, astemizole and a combination of both (2OHOA + astemizole) for 24, 48 or 72 h (Fig. 3A–C). 2OHOA at 200 μM and astemizole at 5 μM significantly reduced cell proliferation after 72 h treatment by 26.7% and 43.2%, respectively (Fig. 3C). Interestingly, the combination of both drugs (200 μM 2OHOA + 5 μM astemizole) significantly reduced cell proliferation by 22%, 41.2% and 54.3% at 24 (Fig. 3A), 48 (Fig. 3B) and 72 h (Fig. 3C), respectively. At 24 and 48 h, the combination of 2OHOA and astemizole induced a higher decrease on cell proliferation than when each drug was applied alone, indicating a synergistic effect (Fig. 3A, B). At 72 h, a small further decrease on cell proliferation was also observed, although was not statistically significant (Fig. 3C).

Fig. 3
figure 3

2OHOA and astemizole synergistically decreases cell proliferation of HEK-293 cells expressing the Kv10.1 channel. AC the effect of 200 µM 2OHOA on cell proliferation was determined using the MTT assay at 24 (A), 48 (B) and 72 h (C) on HEK-293 cells expressing the Kv10.1 channel (n = 6). D Effect of 200 µM 2OHOA on proliferation of HEK-293 cells expressing the non-conducting mutant Kv10.1-F456A (n = 6). E Effect of 200 µM 2OHOA on proliferation of HEK-293 cells not expressing Kv10.1 channels (n = 5). Asterisks indicate significant effects compared with controls (*p < 0.05), # indicate a significant effect of the combination 2OHOA + Astemizole compared with both drugs applied alone (#p < 0.05), NS: Not significant. Data are represented as mean ± SEM

Additionally, we evaluated the effect of 2OHOA on the proliferation of HEK-293 cells expressing the non-conducting Kv10.1-F456A mutant channel (Fig. 3D). The Kv10.1-F456A channel has been reported to induce cell proliferation even though it is unable to conduct ions [38]. After 72 h treatment, 2OHOA reduced cell proliferation by 26% (Fig. 3D), similar to the effect observed on HEK-293 cells expressing the wild type (WT) Kv10.1 channel. Notably, in HEK-293 cells not expressing Kv10.1 channels, 2OHOA does not significantly inhibited cell proliferation (Fig. 3E).

Finally, we determined the effects of 2OHOA and astemizole on the proliferation of MCF-7 cells, a breast cancer cell line that endogenously expresses Kv10.1 channels.

MCF-7 cells were treated with different concentrations of 2OHOA (12.5, 25, 50, 100, 200, 400 and 1000 µM), 5 µM astemizole, and a combination of 200 µM 2OHOA and 5 µM astemizole for 24, 48 and 72 h (Fig. 4). Proliferation of MCF-7 cells was decreased only at high concentrations of 2OHOA (> 400 µM, Fig. 4). Astemizole (5 µM) decreased MCF-7 cells proliferation at 48 and 72 h by 19.4% and 60.9% respectively (Fig. 4B, C), similar to previous reports [39]. Remarkably, as observed in Kv10.1 expressing HEK-293 cells, the combination of 200 µM 2OHOA and 5 µM astemizole has a synergistic effect in reducing proliferation of MCF-7 cells. Under this condition (2OHOA + astemizole), cell proliferation was reduced by 25.8%, 41.7%, and 71.9% at 24, 48 and 72 h, respectively (Fig. 4A–C).

Fig. 4
figure 4

2OHOA and astemizole synergistically decreases MCF-7 cells proliferation. AC proliferation of MCF-7 cells treated with different concentrations of 2OHOA (12.5, 25, 50, 100, 200, 400 and 1000 µM), 5 µM astemizole and the combination 200 µM 2OHOA and 5 µM astemizole determined at 24 (A), 48 (B) and 72 h (C). Asterisks indicate significant effects compared with controls (*p < 0.05; **p < 0.01), # indicates a significant effect of the combination of 200 µM 2OHOA + 5 µM Astemizole compared to 200 µM 2OHOA or 5 µM Astemizole applied alone (#p < 0.05; ##p < 0.01), NS: Not significant. Data are represented as mean ± SEM (n = 5)

4 Discussion

2-hydroxyoleic acid (2OHOA) is a synthetic fatty acid with antitumor properties. In contrast with commonly used anticancer drugs, 2OHOA targets the plasma membrane altering its composition and structure, thereby affecting the functioning of membrane proteins and cell signaling [2,3,4,5,6,7,8,9]. In the present study we found another mechanism of action for the antitumoral effects of 2OHOA, resulting from the modulation of Kv10.1 channels.

2OHOA was rationally designed to treat a condition by modulating membrane lipid composition and structure, the so-called membrane lipid therapy (MLT) [40]. Two main mechanisms have been described for 2OHOA action: (1) either free or in phospholipids, 2OHOA regulates the order of membrane lipids, the membrane structure, and the balance between raft and non-raft domains (type-1 MLT); and (2) by its activation of the sphingomyelin synthase, 2OHOA increases the levels of sphingomyelin, changing the membrane lipid composition (type-2 MLT) [7, 10, 12]. These effects induced by 2OHOA on the plasma membrane could affect the functioning of lipid-sensitive proteins, as is the case of Kv10.1, an ion channel that has been shown to be regulated by different membrane lipids [22, 41]. Notably, the perturbation of membrane structure by methyl-beta-cyclodextrin (MBCD) treatment increases the current density of Kv10.1 channels [22], evidencing the channel sensitivity to alterations on the plasma membrane. Similarly, here we found that 2OHOA application increased the current amplitude of Kv10.1 channels (Fig. 1) and modulate its kinetics and voltage dependence (Fig. 2). The known sensitivity of Kv10.1 to plasma membrane alterations lead us to propose that the effects induced by 2OHOA on the functioning of this channel are likely generated by the type-1 MLT mechanism. Although, our experiments cannot completely discard the tipe-2 MLT mechanism.

Studies have shown that Kv10.1 channel blockage decreases cell proliferation [35], reflecting the importance of ion permeation through this channel on this process. However, non-conducting Kv10.1 mutants also support cell proliferation by regulating intracellular signaling pathways, a process attributed to voltage-dependent changes on the protein conformation rather than ion permeation [34, 38]. In this work, astemizole, a Kv10.1 channel blocker, decreased proliferation of HEK-293 (transfected with Kv10.1) and MCF-7 cells (Figs. 3 and 4), which agree with previous reports [39]. On the other hand, 2OHOA did not block ion conduction through Kv10.1 channels but regulated its voltage-dependent gating; the voltage-dependence of activation was shifted toward negative voltages (Fig. 2A) and the kinetics of channel activation was accelerated (Fig. 2B). 2OHOA induced a reduction of cell proliferation on Kv10.1 expressing cells (Figs. 3 and 4), whereas Kv10.1 non-expressing cells (HEK-293 cells transfected only with EGFP) were not affected by 2OHOA (Fig. 3E). Interestingly, 2OHOA also reduced proliferation of HEK-293 cells expressing the non-conducting Kv10.1-F456A mutant (Fig. 3D). Altogether, these results suggest that 2OHOA could be interfering with a non-conducting function of Kv10.1 channels involved in cell proliferation, possibly, with an intracellular signaling pathway regulated by voltage-dependent changes in the channel conformation.

Remarkably, 2OHOA and astemizole synergistically decreased cell proliferation of Kv10.1 expressing cells (Figs. 3, 4), suggesting that simultaneously targeting the conducting and non-conducting functions of Kv10.1 channels could be a more effective antiproliferative strategy.

In conclusion, 2OHOA decreases cell proliferation by several mechanisms, including the regulation of Kv10.1 channels. Moreover, 2OHOA can act synergistically with drugs that block ion permeation through Kv10.1 channels to reduce more effectively cell proliferation.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.



2-Hydroxyoleic acid


Protein kinase C


Dimethyl sulfoxide


Enhanced green fluorescence protein


3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenylte-trazolium bromide




  1. Barceló F, Prades J, Funari SS, Frau J, Alemany R, Escribá PV (2004) The hypotensive drug 2-hydroxyoleic acid modifies the structural properties of model membranes. Mol Membr Biol 21:261–268.

    Article  CAS  Google Scholar 

  2. Ibarguren M, López DJ, Encinar JA, González-Ros JM, Busquets X, Escribá PV (2013) Partitioning of liquid-ordered/liquid-disordered membrane microdomains induced by the fluidifying effect of 2-hydroxylated fatty acid derivatives. Biochim Biophys Acta 1828:2553–2563.

    Article  CAS  Google Scholar 

  3. Lladó V, López DJ, Ibarguren M, Alonso M, Soriano JB, Escribá PV, Busquets X (2014) Regulation of the cancer cell membrane lipid composition by NaCHOleate: effects on cell signaling and therapeutical relevance in glioma. Biochim Biophys Acta 1838:1619–1627.

    Article  CAS  Google Scholar 

  4. Prades J, Alemany R, Perona JS, Funari SS, Vögler O, Ruiz-Gutiérrez V, Escribá PV, Barceló F (2008) Effects of 2-hydroxyoleic acid on the structural properties of biological and model plasma membranes. Mol Membr Biol 25:46–57.

    Article  CAS  Google Scholar 

  5. Martínez J, Gutiérrez A, Casas J, Lladó V, López-Bellan A, Besalduch J, Dopazo A, Escribá PV (2005) The repression of E2F–1 is critical for the activity of Minerval against cancer. J Pharmacol Exp Ther 315:466–474.

    Article  CAS  Google Scholar 

  6. Martínez J, Vögler O, Casas J, Barceló F, Alemany R, Prades J, Nagy T, Baamonde C, Kasprzyk PG, Terés S, Saus C, Escribá PV (2005) Membrane structure modulation, protein kinase C alpha activation, and anticancer activity of minerval. Mol Pharmacol 67:531–540.

    Article  CAS  Google Scholar 

  7. Piotto S, Trapani A, Bianchino E, Ibarguren M, López DJ, Busquets X, Concilio S (2014) The effect of hydroxylated fatty acid-containing phospholipids in the remodeling of lipid membranes. Biochim Biophys Acta 1838:1509–1517.

    Article  CAS  Google Scholar 

  8. Terés S, Lladó V, Higuera M, Barceló-Coblijn G, Martin ML, Noguera-Salvà MA, Marcilla-Etxenike A, García-Verdugo JM, Soriano-Navarro M, Saus C, Gómez-Pinedo U, Busquets X, Escribá PV (2012) Normalization of sphingomyelin levels by 2-hydroxyoleic acid induces autophagic cell death of SF767 cancer cells. Autophagy 8:1542–1544.

    Article  CAS  Google Scholar 

  9. Torgersen ML, Klokk TI, Kavaliauskiene S, Klose C, Simons K, Skotland T, Sandvig K (2016) The anti-tumor drug 2-hydroxyoleic acid (Minerval) stimulates signaling and retrograde transport. Oncotarget 7:86871–86888.

    Article  Google Scholar 

  10. Barceló-Coblijn G, Martin ML, de Almeida RF, Noguera-Salvà MA, Marcilla-Etxenike A, Guardiola-Serrano F, Lüth A, Kleuser B, Halver JE, Escribá PV (2011) Sphingomyelin and sphingomyelin synthase (SMS) in the malignant transformation of glioma cells and in 2-hydroxyoleic acid therapy. Proc Natl Acad Sci USA 108:19569–19574.

    Article  Google Scholar 

  11. Llado V, Gutierrez A, Martínez J, Casas J, Terés S, Higuera M, Galmés A, Saus C, Besalduch J, Busquets X, Escribá PV (2010) Minerval induces apoptosis in Jurkat and other cancer cells. J Cell Mol Med 14:659–670.

    Article  CAS  Google Scholar 

  12. Escribá PV, Busquets X, Inokuchi J, Balogh G, Török Z, Horváth I, Harwood JL, Vígh L (2015) Membrane lipid therapy: modulation of the cell membrane composition and structure as a molecular base for drug discovery and new disease treatment. Prog Lipid Res 59:38–53.

    Article  CAS  Google Scholar 

  13. Martin ML, Barceló-Coblijn G, de Almeida RF, Noguera-Salvà MA, Terés S, Higuera M, Liebisch G, Schmitz G, Busquets X, Escribá PV (2013) The role of membrane fatty acid remodeling in the antitumor mechanism of action of 2-hydroxyoleic acid. Biochim Biophys Acta 1828:1405–1413.

    Article  CAS  Google Scholar 

  14. Piotto S, Concilio S, Bianchino E, Iannelli P, López DJ, Terés S, Ibarguren M, Barceló-Coblijn G, Martin ML, Guardiola-Serrano F, Alonso-Sande M, Funari SS, Busquets X, Escribá PV (2014) Differential effect of 2-hydroxyoleic acid enantiomers on protein (sphingomyelin synthase) and lipid (membrane) targets. Biochim Biophys Acta 1838:1628–1637.

    Article  CAS  Google Scholar 

  15. Piotto S, Sessa L, Iannelli P, Concilio S (2017) Computational study on human sphingomyelin synthase 1 (hSMS1). Biochim Biophys Acta 1859:1517–1525.

    Article  CAS  Google Scholar 

  16. Marcilla-Etxenike A, Martín ML, Noguera-Salvà MA, García-Verdugo JM, Soriano-Navarro M, Dey I, Escribá PV, Busquets X (2012) 2-Hydroxyoleic acid induces ER stress and autophagy in various human glioma cell lines. PLoS ONE 7:e48235.

    Article  CAS  Google Scholar 

  17. Terés S, Lladó V, Higuera M, Barceló-Coblijn G, Martin ML, Noguera-Salvà MA, Marcilla-Etxenike A, García-Verdugo JM, Soriano-Navarro M, Saus C, Gómez-Pinedo U, Busquets X, Escribá PV (2012) 2-Hydroxyoleate, a nontoxic membrane binding anticancer drug, induces glioma cell differentiation and autophagy. Proc Natl Acad Sci USA 109:8489–8494.

    Article  Google Scholar 

  18. Mishra K, Péter M, Nardiello AM, Keller G, Llado V, Fernandez-Garcia P, Kahlert UD, Barasch D, Saada A, Török Z, Balogh G, Escriba PV, Piotto S, Kakhlon O (2022) Multifaceted analyses of isolated mitochondria establish the anticancer drug 2-hydroxyoleic acid as an inhibitor of substrate oxidation and an activator of complex IV-dependent state 3 respiration. Cells 11:578.

    Article  CAS  Google Scholar 

  19. Gu RX, de Groot BL (2020) Lipid-protein interactions modulate the conformational equilibrium of a potassium channel. Nat Commun 11:2162.

    Article  CAS  Google Scholar 

  20. Zakany F, Kovacs T, Panyi G, Varga Z (2020) Direct and indirect cholesterol effects on membrane proteins with special focus on potassium channels. Biochim Biophys Acta 1865:158706.

    Article  CAS  Google Scholar 

  21. Cornelius F, Habeck M, Kanai R, Toyoshima C, Karlish SJ (2015) General and specific lipid-protein interactions in Na, K-ATPase. Biochim Biophys Acta 1848:1729–1743.

    Article  CAS  Google Scholar 

  22. Jiménez-Garduño AM, Mitkovski M, Alexopoulos IK, Sánchez A, Stühmer W, Pardo LA, Ortega A (2014) KV10.1 K(+)-channel plasma membrane discrete domain partitioning and its functional correlation in neurons. Biochim Biophys Acta 1838:921–931.

    Article  CAS  Google Scholar 

  23. Cázares-Ordoñez V, Pardo LA (2017) Kv10.1 potassium channel: from the brain to the tumors. Biochem Cell Biol 95:531–536.

    Article  CAS  Google Scholar 

  24. Ouadid-Ahidouch H, Ahidouch A, Pardo LA (2016) Kv10.1 K(+) channel: from physiology to cancer. Pflugers Archiv 468:751–762.

    Article  CAS  Google Scholar 

  25. Hemmerlein B, Weseloh RM, Mello de Queiroz F, Knötgen H, Sánchez A, Rubio ME, Martin S, Schliephacke T, Jenke M, Heinz-Joachim-Radzun SW, Pardo LA (2006) Overexpression of Eag1 potassium channels in clinical tumours. Mol Cancer 5:41.

    Article  CAS  Google Scholar 

  26. Pardo LA, del Camino D, Sánchez A, Alves F, Brüggemann A, Beckh S, Stühmer W (1999) Oncogenic potential of EAG K(+) channels. EMBO J 18:5540–5547.

    Article  CAS  Google Scholar 

  27. Pardo LA, Stühmer W (2014) The roles of K(+) channels in cancer. Nat Rev Cancer 14:39–48.

    Article  CAS  Google Scholar 

  28. Ludwig J, Terlau H, Wunder F, Brüggemann A, Pardo LA, Marquardt A, Stühmer W, Pongs O (1994) Functional expression of a rat homologue of the voltage gated either á go-go potassium channel reveals differences in selectivity and activation kinetics between the Drosophila channel and its mammalian counterpart. EMBO J 13:4451–4458.

    Article  CAS  Google Scholar 

  29. Díaz L, Ceja-Ochoa I, Restrepo-Angulo I, Larrea F, Avila-Chávez E, García-Becerra R, Borja-Cacho E, Barrera D, Ahumada E, Gariglio P, Alvarez-Rios E, Ocadiz-Delgado R, Garcia-Villa E, Hernández-Gallegos E et al (2009) Estrogens and human papilloma virus oncogenes regulate human ether-à-go-go-1 potassium channel expression. Cancer Res 69:3300–3307.

    Article  CAS  Google Scholar 

  30. Occhiodoro T, Bernheim L, Liu JH, Bijlenga P, Sinnreich M, Bader CR, Fischer-Lougheed J (1998) Cloning of a human ether-a-go-go potassium channel expressed in myoblasts at the onset of fusion. FEBS Let 434:177–182.

    Article  CAS  Google Scholar 

  31. Gavrilova-Ruch O, Schönherr K, Gessner G, Schönherr R, Klapperstück T, Wohlrab W, Heinemann SH (2002) Effects of imipramine on ion channels and proliferation of IGR1 melanoma cells. J Membr Biol 188:137–149.

    Article  CAS  Google Scholar 

  32. Urrego D, Tomczak AP, Zahed F, Stühmer W, Pardo LA (2014) Potassium channels in cell cycle and cell proliferation. Philos Trans R Soc Lond B Biol Sci 369:20130094.

    Article  Google Scholar 

  33. Weber C, de Queiroz FM, Downie BR, Suckow A, Stühmer W, Pardo LA (2006) Silencing the activity and proliferative properties of the human EagI Potassium Channel by RNA Interference. J Biol Chem 281:13030–13037.

    Article  CAS  Google Scholar 

  34. Downie BR, Sánchez A, Knötgen H, Contreras-Jurado C, Gymnopoulos M, Weber C, Stühmer W, Pardo LA (2008) Eag1 expression interferes with hypoxia homeostasis and induces angiogenesis in tumors. J Biol Chem 283:36234–36240.

    Article  CAS  Google Scholar 

  35. Agarwal JR, Griesinger F, Stühmer W, Pardo LA (2010) The potassium channel Ether à go-go is a novel prognostic factor with functional relevance in acute myeloid leukemia. Mol cancer 9:18.

    Article  CAS  Google Scholar 

  36. Hammadi M, Chopin V, Matifat F, Dhennin-Duthille I, Chasseraud M, Sevestre H, Ouadid-Ahidouch H (2012) Human ether à-gogo K(+) channel 1 (hEag1) regulates MDA-MB-231 breast cancer cell migration through Orai1-dependent calcium entry. J Cell Physiol 227:3837–3846.

    Article  CAS  Google Scholar 

  37. Ouadid-Ahidouch H, Ahidouch A (2008) K+ channel expression in human breast cancer cells: involvement in cell cycle regulation and carcinogenesis. J Membr Biol 221:1–6.

    Article  CAS  Google Scholar 

  38. Hegle AP, Marble DD, Wilson GF (2006) A voltage-driven switch for ion-independent signaling by ether-à-go-go K+ channels. Proc Natl Acad Sci U S A 103:2886–2891.

    Article  CAS  Google Scholar 

  39. Ouadid-Ahidouch H, Le Bourhis X, Roudbaraki M, Toillon RA, Delcourt P, Prevarskaya N (2001) Changes in the K+ current-density of MCF-7 cells during progression through the cell cycle: possible involvement of a h-ether.a-gogo K+ channel. Recept Channels 7:345–356

    CAS  Google Scholar 

  40. Escribá PV (2017) Membrane-lipid therapy: a historical perspective of membrane-targeted therapies—from lipid bilayer structure to the pathophysiological regulation of cells. Biochim Biophys Acta 1859:1493–1506.

    Article  CAS  Google Scholar 

  41. Delgado-Ramírez M, López-Izquierdo A, Rodríguez-Menchaca AA (2018) Dual regulation of hEAG1 channels by phosphatidylinositol 4,5-bisphosphate. Biochem Biophys Res Commun 503:2531–2535.

    Article  CAS  Google Scholar 

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We thank Xóchitl Ordaz Ruiz for technical assistance.


This work was supported by the SEP-CONACYT grant CB-284443 (to AAR-M), and Universidad Autónoma de San Luis Potosí C18-FRC-08-03.03 (to AAR-M). RM-Z were supported by a Graduate Student Fellowship (#461406) from CONACYT, México.

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RM-Z and AAR-M designed the study. RM-Z conducted the experiments and collected the data. RM-Z and AAR-M analyzed the data and drafted the manuscript. Both authors read and approved the final manuscript.

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Correspondence to Aldo A. Rodríguez-Menchaca.

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Morán-Zendejas, R., Rodríguez-Menchaca, A.A. The anti-tumor drug 2-hydroxyoleic acid regulates the oncogenic potassium channel Kv10.1. Beni-Suef Univ J Basic Appl Sci 12, 15 (2023).

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  • Potassium channels
  • Synthetic lipids
  • Electrophysiology
  • Cell proliferation