Involvement of potassium channels in the progression of cancer to a more malignant phenotype

Comes, Núria; Serrano-Albarrás, Antonio; Capera, Jesusa; Serrano-Novillo, Clara; Condom, Enric; Cajal, Santiago Ramón y; Ferreres, Joan Carles; Felipe, Antônio

doi:10.1016/j.bbamem.2014.12.008

Cited by 111 publications

(95 citation statements)

References 262 publications

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“…K + channels can be modulated by a wide range of chemical and physical stimuli, including acidification [32][33][34] and hypoxia [35]. Interestingly, the pharmacologic inhibition of certain K + channels exerted antitumor activity in certain cases [36], suggesting an increased channel activity in tumor cells compared with non-tumor cells [30,31]. Such effect could explain the existence of a larger amount of potassium adducts in the viable areas of the xenograft, as PC species (usually in the outer leaflet of the plasma membrane) would find more potassium cations to interact with.…”

Section: Resultsmentioning

confidence: 99%

“…The acid microenvironment will certainly have an effect on all ionic channels responsible for the maintenance of the strictly regulated intracellular milieu. In this context, it is known that different types of K + channels are unequivocally associated with malignant progression [30,31]. K + channels can be modulated by a wide range of chemical and physical stimuli, including acidification [32][33][34] and hypoxia [35].…”

Section: Resultsmentioning

confidence: 99%

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Identification of Biomarkers of Necrosis in Xenografts Using Imaging Mass Spectrometry

Fernández

Garate

Lage

et al. 2015

J. Am. Soc. Mass Spectrom.

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Abstract. Xenografts are commonly used to test the effect of new drugs on human cancer. However, because of their heterogeneity, analysis of the results is often controversial. Part of the problem originates in the existence of tumor cells at different metabolic stages: from metastatic to necrotic cells, as it happens in real tumors. Imaging mass spectrometry is an excellent solution for the analysis of the results as it yields detailed information not only on the composition of the tissue but also on the distribution of the biomolecules within the tissue. Here, we use imaging mass spectrometry to determine the distribution of phosphatidylcholine (PC), phosphatidylethanolamine (PE), and their plasmanyl-and plasmenylether derivatives (PC-P/O and PE-P/O) in xenografts of five different tumor cell lines: A-549, NCI-H1975, BX-PC3, HT29, and U-87 MG. The results demonstrate that the necrotic areas showed a higher abundance of Na + adducts and of PC-P/O species, whereas a large abundance of PE-P/O species was found in all the xenografts. Thus, the PC/PC-ether and Na + /K + ratios may highlight the necrotic areas while an increase on the number of PEether species may be pointing to the existence of viable tumor tissues. Furthermore, the existence of important changes in the concentration of Na + and K + adducts between different tissues has to be taken into account while interpreting the imaging mass spectrometry results.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Identification of Biomarkers of Necrosis in Xenografts Using Imaging Mass Spectrometry

Fernández

Garate

Lage

et al. 2015

J. Am. Soc. Mass Spectrom.

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“…Although the present findings are not adequate to answer these questions, in those tissues where we have directly recorded BK currents or tested for coassembly between LRRC26 and BK α-subunits, LRRC26 appears to be a critical regulatory component of BK channels. Given that a large number of ion channels have been implicated in tumor growth regulation, including KCa3.1 (47,48), calcium channels (49), sodium channels (50), and a variety of K + channels (51,52), these associations raise the possibility that specific ion channels per se may not be intrinsically related to tumor growth regulation, but that some aspect of membrane potential regulation, perhaps linked to cell cycle regulation, is the determinant of whether a given ion channel may promote or impede tumor growth.…”

Section: Potential Roles Of Lrrc26-containing Bk Channels In Tumor Grmentioning

confidence: 99%

Knockout of the LRRC26 subunit reveals a primary role of LRRC26-containing BK channels in secretory epithelial cells

Yang

González-Pérez

Mukaibo

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Leucine-rich-repeat-containing protein 26 (LRRC26) is the regulatory γ1 subunit of Ca 2+ -and voltage-dependent BK-type K + channels. BK channels that contain LRRC26 subunits are active near normal resting potentials even without Ca 2+ , suggesting they play unique physiological roles, likely limited to very specific cell types and cellular functions. By using Lrrc26 KO mice with a β-gal reporter, Lrrc26 promoter activity is found in secretory epithelial cells, especially acinar epithelial cells in lacrimal and salivary glands, and also goblet and Paneth cells in intestine and colon, although absent from neurons. We establish the presence of LRRC26 protein in eight secretory tissues or tissues with significant secretory epithelium and show that LRRC26 protein coassembles with the pore-forming BK α-subunit in at least three tissues: lacrimal gland, parotid gland, and colon. In lacrimal, parotid, and submandibular gland acinar cells, LRRC26 KO shifts BK gating to be like α-subunit-only BK channels. Finally, LRRC26 KO mimics the effect of SLO1/BK KO in reducing [K + ] in saliva. LRRC26-containing BK channels are competent to contribute to resting K + efflux at normal cell membrane potentials with resting cytosolic Ca 2+ concentrations and likely play a critical physiological role in supporting normal secretory function in all secretory epithelial cells.L arge-conductance, voltage-and Ca 2+ -regulated BK-type channels are widely expressed proteins, found not only in excitable cells, such as neurons, muscle, and endocrine cells, but also nonexcitable cells, including salivary (1) and lacrimal gland (2) acinar cells, and colonic crypt cells (3). Given the almost ubiquitous expression of BK channels among cells that play quite distinct physiological roles, it is particularly important to define the specific properties of BK channels in a given cell type and determine what the specific physiological role played by BK channels in a given cell may be. A hallmark of BK channels is their dual regulation by both membrane voltage and cytosolic Ca 2+ (4), both properties embedded within the tetramer of pore-forming α-subunits of each BK channel (5). However, the specific range of voltages over which a BK channel is active at a given Ca 2+ concentration is markedly dependent on the identity of regulatory subunits that can coassemble with the α-subunit in the mature channel complex. Of the two families of known BK regulatory subunits, β (6-11) and γ (12-14), an important feature of many of these subunits is the ability to shift the range of activation voltages at a given Ca 2+ . Although there is growing information about the loci of expression and functional roles of BK channels containing specific β-subunits (15), much less is known about those BK channels containing the γ1 (LRRC26, leucine-rich-repeat-containing subunit 26) subunit. However, LRRC26 is particularly fascinating because it causes the largest shift in BK gating (approximately −120 mV) of any known non-pore-forming regulatory subunit, resulting in BK channels that...

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“…To detect channels in membrane enriched fractions we used the protocol reported previously [7]. Briefly, cells were seeded in a 100 mm tissue culture dish for 24 hrs.…”

Section: Cell Membrane Fraction Enrichmentmentioning

confidence: 99%

“…The Kv1.3 channel, belonging to the potassium (K + ) channels shaker family, has been demonstrated to be expressed in several cancer cell lines [5][6][7]. In addition to the plasma membrane, Kv1.3 was identified in the inner mitochondrial membrane (IMM), where it was shown to play a critical role in the induction of apoptosis [8].…”

Section: Introductionmentioning

confidence: 99%

Targeting the Potassium Channel Kv1.3 Kills Glioblastoma Cells

et al. 2017

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Background/Aims: Glioblastoma (GBM) is one of the most aggressive cancers, counting for a high number of the newly diagnosed patients with central nervous system (CNS) cancers in the United States and Europe. Major features of GBM include aggressive and invasive growth as well as a high resistance to treatment. Kv1.3, a potassium channel of the shaker family, is expressed in the inner mitochondrial membrane of many cancer cells. Inhibition of mitochondrial Kv1.3 was shown to induce apoptosis in several tumor cells at doses that were not lethal for normal cells. Methods: We investigated the expression of Kv1.3 in different glioma cell lines by immunocytochemistry, western blotting and electron microscopy and analyzed the effect of newly synthesized, mitochondria-targeted, Kv1.3 inhibitors on the induction of cell death in these cells. Finally, we performed in vivo studies on glioma bearing mice. Results: Here, we report that Kv1.3 is expressed in mitochondria of human and murine GL261, A172 and LN308 glioma cells. Treatment with the novel Kv1.3 inhibitors PAPTP or PCARBTP as well as with clofazimine induced massive cell death in glioma cells, while Psora-4 and PAP-1 were almost without effect. However, in vivo experiments revealed that the drugs had no effect on orthotopic brain tumors in vivo. Conclusion: These data serve as proof of principle that Kv1.3 inhibitors kills GBM cells, but drugs that act in vivo against glioblastoma must be developed to translate these findings in vivo.

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Involvement of potassium channels in the progression of cancer to a more malignant phenotype

Cited by 111 publications

References 262 publications

Identification of Biomarkers of Necrosis in Xenografts Using Imaging Mass Spectrometry

Identification of Biomarkers of Necrosis in Xenografts Using Imaging Mass Spectrometry

Knockout of the LRRC26 subunit reveals a primary role of LRRC26-containing BK channels in secretory epithelial cells

Targeting the Potassium Channel Kv1.3 Kills Glioblastoma Cells

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