Special Issue "Ion Channels in Cancer"

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (15 December 2018)

Special Issue Editor

Guest Editor
Prof. Dr. Stephan M. Huber

Department of Radiation Oncology, University of Tübingen, Hoppe-Seyler-Str. 3, 72076 Tübingen, Germany
Website | E-Mail
Interests: glioma; radiation physiology; electro- and Ca2+ signaling; ion channels in tumor biology

Special Issue Information

Dear Colleagues,

Virtually all cellular processes rely on ion channels. By modifying the chemistry, electricity and mechanics of every cell, ion channels seem to have a plethora of tools to regulate the activities of downstream effectors molecules and to interfere with biochemical signaling. In addition, recent observations suggest that ion channels may signal via direct molecular interaction in macromolecular complexes, or even as transcription factor.

A hallmark of tumor cells is an—as compared to the non-transformed parental cells—aberrant expression and activity pattern of ion channels. Notably, the oncogenesis-associated changes in ion channel expression and activity are not just an epiphenomenon of neoplastic transformation. This conclusion can be drawn from the fact that experimental interference with ion channels may impair clonogenic survival, cell cycling, invasive behavior, resistance to hypoxia, or metabolic adaptations of tumor cells. Instead, accumulating pieces of evidence suggest that aberrant ion channel activity directly contributes to programming and execution of oncogenic processes.

Moreover, ion channels have been demonstrated to become activated during the stress response of tumor cells and to confer therapy resistance. In combination with their tumor-associated expression, ion channels, therefore, seem to be ideal targets to sensitize tumor cells to anti-tumor therapy. As a matter of fact, many approved drugs modify on purpose or as side effect ion channels suggesting that the clinical translation of pharmacological ion channel targeting is feasible.

This Special Issue will highlight the function of ion channels in tumor biology. A better knowledge about the role of ion channels in, e.g., the maintenance of a stem cell-like phenotype, in adaptation to the microenvironment including hypoxia, in tissue infiltration and metastasis, in the crosstalk with endothelial, stroma or bone marrow-derived cells, in resistance to radio- or chemotherapy, or in evasion from immune surveillance is a prerequisite to develop intelligent new concepts of anti-tumor therapy that combine ion channel targeting with established therapy modalities.

Prof. Dr. Stephan M. Huber
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Oncochannels
  • Electro- and Ca2+ signaling
  • Cancer stem cells
  • Radiochemotherapy
  • Immunotherapy
  • Ion channel targeting

Published Papers (21 papers)

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Research

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Open AccessArticle NMDA Receptor Signaling Mediates cFos Expression via Top2β-Induced DSBs in Glioblastoma Cells
Cancers 2019, 11(3), 306; https://doi.org/10.3390/cancers11030306
Received: 18 January 2019 / Revised: 20 February 2019 / Accepted: 27 February 2019 / Published: 5 March 2019
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Abstract
The activation of Ca2+-permeable N-methyl-D-aspartic acid (NMDA) receptor channels (NMDARs) is crucial for the development and survival of neurons, but many cancers use NMDAR-mediated signaling as well, enhancing the growth and invasiveness of tumors. Thus, NMDAR-dependent pathways emerge as a [...] Read more.
The activation of Ca2+-permeable N-methyl-D-aspartic acid (NMDA) receptor channels (NMDARs) is crucial for the development and survival of neurons, but many cancers use NMDAR-mediated signaling as well, enhancing the growth and invasiveness of tumors. Thus, NMDAR-dependent pathways emerge as a promising target in cancer therapy. Here, we use the LN229 and U-87MG glioblastoma multiforme (GBM) cells and immunofluorescence staining of 53BP1 to analyze NMDAR-induced DNA double-strand breaks (DSBs), which represent an important step in the NMDAR signaling pathway in neurons by facilitating the expression of early response genes. Our results show that NMDAR activation leads to the induction of DSBs in a subpopulation of glioma cells. In a further analogy to neurons, our results demonstrate that the induction of DSBs in LN229 cells is dependent on the activity of topoisomerase IIβ (Top2β). Western blot analysis revealed that the inhibition of NMDARs, cAMP-responsive element binding transcription factor (CREB) and Top2β decreased the expression of the proto-oncogene cFos. Knockdown of Top2β with siRNAs resulted in a downregulation of cFos and increased the radiosensitivity of LN229 cells in clonogenic survival. We also observed impaired cFos expression upon NMDAR and Top2β inhibition in a primary GBM cell line, suggesting that NMDAR signaling may be widely used by GBMs, demonstrating the potential of targeting NMDAR signaling proteins for GBM therapy. Full article
(This article belongs to the Special Issue Ion Channels in Cancer)
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Open AccessArticle Role of Calcium Signaling in GA101-Induced Cell Death in Malignant Human B Cells
Cancers 2019, 11(3), 291; https://doi.org/10.3390/cancers11030291
Received: 11 January 2019 / Revised: 15 February 2019 / Accepted: 22 February 2019 / Published: 1 March 2019
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Abstract
GA101/obinutuzumab is a novel type II anti-CD20 monoclonal antibody (mAb), which is more effective than rituximab (RTX) in preclinical and clinical studies when used in combination with chemotherapy. Ca2+ signaling was shown to play a role in RTX-induced cell death. This report [...] Read more.
GA101/obinutuzumab is a novel type II anti-CD20 monoclonal antibody (mAb), which is more effective than rituximab (RTX) in preclinical and clinical studies when used in combination with chemotherapy. Ca2+ signaling was shown to play a role in RTX-induced cell death. This report concerns the effect of GA101 on Ca2+ signaling and its involvement in the direct cell death induced by GA101. We reveal that GA101 triggered an intracellular Ca2+ increase by mobilizing intracellular Ca2+ stores and activating Orai1-dependent Ca2+ influx in non-Hodgkin lymphoma cell lines and primary B-Cell Chronic Lymphocytic Leukemia (B-CLL) cells. According to the cell type, Ca2+ was mobilized from two distinct intracellular compartments. In Raji, BL2, and B-CLL cells, GA101 induced a Ca2+ release from lysosomes, leading to the subsequent lysosomal membrane permeabilization and cell death. Inhibition of this calcium signaling reduced GA101-induced cell death in these cells. In SU-DHL-4 cells, GA101 mobilized Ca2+ from the endoplasmic reticulum (ER). Inhibition of ER replenishment, by blocking Orai1-dependent Ca2+ influx, led to an ER stress and unfolded protein response (UPR) which sensitized these cells to GA101-induced cell death. These results revealed the central role of Ca2+ signaling in GA101’s action mechanism, which may contribute to designing new rational drug combinations improving its clinical efficacy. Full article
(This article belongs to the Special Issue Ion Channels in Cancer)
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Open AccessArticle Radiation Increases Functional KCa3.1 Expression and Invasiveness in Glioblastoma
Cancers 2019, 11(3), 279; https://doi.org/10.3390/cancers11030279
Received: 30 December 2018 / Revised: 25 January 2019 / Accepted: 20 February 2019 / Published: 26 February 2019
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Abstract
Glioblastoma (GBM) is a deadly brain tumor, with fast recurrence even after surgical intervention, radio- and chemotherapies. One of the reasons for relapse is the early invasion of surrounding brain parenchyma by GBM, rendering tumor eradication difficult. Recent studies demonstrate that, in addition [...] Read more.
Glioblastoma (GBM) is a deadly brain tumor, with fast recurrence even after surgical intervention, radio- and chemotherapies. One of the reasons for relapse is the early invasion of surrounding brain parenchyma by GBM, rendering tumor eradication difficult. Recent studies demonstrate that, in addition to eliminate possible residual tumoral cells after surgery, radiation stimulates the infiltrative behavior of GBM cells. The intermediate conductance of Ca2+-activated potassium channels (KCa3.1) play an important role in regulating the migration of GBM. Here, we show that high dose radiation of patient-derived GBM cells increases their invasion, and induces the transcription of key genes related to these functions, including the IL-4/IL-4R pair. In addition, we demonstrate that radiation increases the expression of KCa3.1 channels, and that their pharmacological inhibition counteracts the pro-invasive phenotype induced by radiation in tumor cells. Our data describe a possible approach to treat tumor resistance that follows radiation therapy in GBM patients. Full article
(This article belongs to the Special Issue Ion Channels in Cancer)
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Open AccessArticle ORAI1 and ORAI3 in Breast Cancer Molecular Subtypes and the Identification of ORAI3 as a Hypoxia Sensitive Gene and a Regulator of Hypoxia Responses
Cancers 2019, 11(2), 208; https://doi.org/10.3390/cancers11020208
Received: 3 January 2019 / Revised: 1 February 2019 / Accepted: 4 February 2019 / Published: 11 February 2019
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Abstract
The remodeling of specific calcium-permeable ion channels is a feature of some breast cancer subtypes. ORAI1 is a protein that forms a calcium-permeable ion channel responsible for store-operated calcium entry (SOCE) in a variety of cell types. ORAI3, a related isoform, is not [...] Read more.
The remodeling of specific calcium-permeable ion channels is a feature of some breast cancer subtypes. ORAI1 is a protein that forms a calcium-permeable ion channel responsible for store-operated calcium entry (SOCE) in a variety of cell types. ORAI3, a related isoform, is not a regulator of SOCE in most cell types. However, ORAI3 does control SOCE in many estrogen receptor-positive breast cancer cell lines, where it also controls proliferation. ORAI1 is a well-characterized regulator of the proliferation and migration of many basal breast cancer cells; however, the role of ORAI3 in these types of breast cancer cells remains unclear. Here, we sought to define ORAI1 and ORAI3 expression in breast cancer cell lines of different molecular subtypes and assess the potential role and regulation of ORAI3 in basal breast cancer cells. Our study demonstrates that elevated ORAI1 is a feature of basal-like breast cancers, while elevated ORAI3 is a feature of luminal breast cancers. Intriguingly, we found that ORAI3 is over-expressed in the mesenchymal subtype of triple-negative breast cancer. Given this, we assessed ORAI3 levels in the presence of two inducers of the mesenchymal phenotype, hypoxia and epidermal growth factor (EGF). Hypoxia induced ORAI3 levels in basal breast cancer cell lines through a pathway involving hypoxia-inducible factor-1 alpha (HIF1α. The silencing of ORAI3 attenuated hypoxia-associated phosphorylation of the EGF receptor (EGFR) and the expression of genes associated with cell migration and inflammatory/immune responses in the MDA-MB-468 model of basal breast cancer. Although elevated ORAI3 levels were not associated with survival; basal, estrogen receptor-negative and triple-negative breast cancers with high ORAI3 and low ORAI1 levels were associated with poorer clinical outcomes. This study defines ORAI3 as a potential fine-tuner for processes relevant to the progression of basal breast cancers. Full article
(This article belongs to the Special Issue Ion Channels in Cancer)
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Open AccessArticle Zoledronic Acid Modulation of TRPV1 Channel Currents in Osteoblast Cell Line and Native Rat and Mouse Bone Marrow-Derived Osteoblasts: Cell Proliferation and Mineralization Effect
Cancers 2019, 11(2), 206; https://doi.org/10.3390/cancers11020206
Received: 21 December 2018 / Revised: 5 February 2019 / Accepted: 6 February 2019 / Published: 11 February 2019
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Abstract
Bisphosphonates (BPs) reduce bone pain and fractures by balancing the osteoblast/osteoclast ratio. The behavior of ion channels in the presence of BPs is not known. To investigate this, the effect of zoledronic acid BP (ZOL) (3 × 10−8 to 5 × 10 [...] Read more.
Bisphosphonates (BPs) reduce bone pain and fractures by balancing the osteoblast/osteoclast ratio. The behavior of ion channels in the presence of BPs is not known. To investigate this, the effect of zoledronic acid BP (ZOL) (3 × 10−8 to 5 × 10−4 M) treatment, on ion channels, cell proliferation, and mineralization, has been investigated on preosteoclast-like cells, RAW264.7, preosteoblast-like cells MC3T3-E1, and rat/mouse native bone marrow-derived osteoblasts. In whole-cell patch clamp on cell line- and bone marrow-derived osteoblasts, ZOL potentiated outward currents. On RAW264.7, ZOL (10−4 M)-evoked current was reduced by the Kv channel blocker tetraethylammonium hydrochloride (TEA), but not by the selective TRPV1-channel antagonist capsazepine. On MC3T3-E1 cells and bone marrow-derived osteoblasts, ZOL-evoked current (5 × 10−8 to 10−4 M) was reduced by capsazepine, whereas the selective TRPV1-channel agonist capsaicin potentiated the control current. In the cell proliferation assay, 72 h incubation of RAW264.7 and MC3T3-E1 cells with ZOL reduced proliferation, with IC50 values of 2.62 × 10−7 M and 2.02 × 10−5 M, respectively. Mineralization of MC3T3-E1 cells and bone marrow-derived osteoblasts was observed in the presence of capsaicin and ZOL (5 × 10−8–10−7 M); ZOL effects were antagonized by capsazepine. In summary, the ZOL-induced activation of TRPV1 channel mediates the mineralization of osteoblasts and counterbalances the antiproliferative effects, increasing the IC50. This mechanism is not operative in osteoclasts lacking the TRPV1 channel. Full article
(This article belongs to the Special Issue Ion Channels in Cancer)
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Open AccessFeature PaperArticle The Activity of KV11.1 Potassium Channel Modulates F-Actin Organization During Cell Migration of Pancreatic Ductal Adenocarcinoma Cells
Cancers 2019, 11(2), 135; https://doi.org/10.3390/cancers11020135
Received: 21 December 2018 / Revised: 16 January 2019 / Accepted: 17 January 2019 / Published: 23 January 2019
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Abstract
Cell migration exerts a pivotal role in tumor progression, underlying cell invasion and metastatic spread. The cell migratory program requires f-actin re-organization, generally coordinated with the assembly of focal adhesions. Ion channels are emerging actors in regulating cell migration, through different mechanisms. We [...] Read more.
Cell migration exerts a pivotal role in tumor progression, underlying cell invasion and metastatic spread. The cell migratory program requires f-actin re-organization, generally coordinated with the assembly of focal adhesions. Ion channels are emerging actors in regulating cell migration, through different mechanisms. We studied the role of the voltage dependent potassium channel KV11.1 on cell migration of pancreatic ductal adenocarcinoma (PDAC) cells, focusing on its effects on f-actin organization and dynamics. Cells were cultured either on fibronectin (FN) or on a desmoplastic matrix (DM) with the addition of a conditioned medium produced by pancreatic stellate cells (PSC) maintained in hypoxia (Hypo-PSC-CM), to better mimic the PDAC microenvironment. KV11.1 was essential to maintain stress fibers in a less organized arrangement in cells cultured on FN. When PDAC cells were cultured on DM plus Hypo-PSC-CM, KV11.1 activity determined the organization of cortical f-actin into sparse and long filopodia, and allowed f-actin polymerization at a high speed. In both conditions, blocking KV11.1 impaired PDAC cell migration, and, on cells cultured onto FN, the effect was accompanied by a decrease of basal intracellular Ca2+ concentration. We conclude that KV11.1 is implicated in sustaining pro-metastatic signals in pancreatic cancer, through a reorganization of f-actin in stress fibers and a modulation of filopodia formation and dynamics. Full article
(This article belongs to the Special Issue Ion Channels in Cancer)
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Open AccessArticle Alternating Electric Fields (TTFields) Activate Cav1.2 Channels in Human Glioblastoma Cells
Cancers 2019, 11(1), 110; https://doi.org/10.3390/cancers11010110
Received: 25 October 2018 / Revised: 16 December 2018 / Accepted: 15 January 2019 / Published: 18 January 2019
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Abstract
Tumor treating fields (TTFields) represent a novel FDA-approved treatment modality for patients with newly diagnosed or recurrent glioblastoma multiforme. This therapy applies intermediate frequency alternating electric fields with low intensity to the tumor volume by the use of non-invasive transducer electrode arrays. Mechanistically, [...] Read more.
Tumor treating fields (TTFields) represent a novel FDA-approved treatment modality for patients with newly diagnosed or recurrent glioblastoma multiforme. This therapy applies intermediate frequency alternating electric fields with low intensity to the tumor volume by the use of non-invasive transducer electrode arrays. Mechanistically, TTFields have been proposed to impair formation of the mitotic spindle apparatus and cytokinesis. In order to identify further potential molecular targets, here the effects of TTFields on Ca2+-signaling, ion channel activity in the plasma membrane, cell cycle, cell death, and clonogenic survival were tested in two human glioblastoma cell lines in vitro by fura-2 Ca2+ imaging, patch-clamp cell-attached recordings, flow cytometry and pre-plated colony formation assay. In addition, the expression of voltage-gated Ca2+ (Cav) channels was determined by real-time RT-PCR and their significance for the cellular TTFields response defined by knock-down and pharmacological blockade. As a result, TTFields stimulated in a cell line-dependent manner a Cav1.2-mediated Ca2+ entry, G1 or S phase cell cycle arrest, breakdown of the inner mitochondrial membrane potential and DNA degradation, and/or decline of clonogenic survival suggesting a tumoricidal action of TTFields. Moreover, inhibition of Cav1.2 by benidipine aggravated in one glioblastoma line the TTFields effects suggesting that Cav1.2-triggered signaling contributes to cellular TTFields stress response. In conclusion, the present study identified Cav1.2 channels as TTFields target in the plasma membrane and provides the rationale to combine TTFields therapy with Ca2+ antagonists that are already in clinical use. Full article
(This article belongs to the Special Issue Ion Channels in Cancer)
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Open AccessArticle Inhibition of Pannexin 1 Reduces the Tumorigenic Properties of Human Melanoma Cells
Cancers 2019, 11(1), 102; https://doi.org/10.3390/cancers11010102
Received: 18 December 2018 / Revised: 9 January 2019 / Accepted: 10 January 2019 / Published: 16 January 2019
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Abstract
Pannexin 1 (PANX1) is a channel-forming glycoprotein expressed in many tissues including the skin. PANX1 channels allow the passage of ions and molecules up to 1 kDa, including ATP and other metabolites. In this study, we show that PANX1 is highly expressed in [...] Read more.
Pannexin 1 (PANX1) is a channel-forming glycoprotein expressed in many tissues including the skin. PANX1 channels allow the passage of ions and molecules up to 1 kDa, including ATP and other metabolites. In this study, we show that PANX1 is highly expressed in human melanoma tumors at all stages of disease progression, as well as in patient-derived cells and established melanoma cell lines. Reducing PANX1 protein levels using shRNA or inhibiting channel function with the channel blockers, carbenoxolone (CBX) and probenecid (PBN), significantly decreased cell growth and migration, and increased melanin production in A375-P and A375-MA2 cell lines. Further, treatment of A375-MA2 tumors in chicken embryo xenografts with CBX or PBN significantly reduced melanoma tumor weight and invasiveness. Blocking PANX1 channels with PBN reduced ATP release in A375-P cells, suggesting a potential role for PANX1 in purinergic signaling of melanoma cells. In addition, cell-surface biotinylation assays indicate that there is an intracellular pool of PANX1 in melanoma cells. PANX1 likely modulates signaling through the Wnt/β-catenin pathway, because β-catenin levels were significantly decreased upon PANX1 silencing. Collectively, our findings identify a role for PANX1 in controlling growth and tumorigenic properties of melanoma cells contributing to signaling pathways that modulate melanoma progression. Full article
(This article belongs to the Special Issue Ion Channels in Cancer)
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Open AccessArticle Inhibition of Polyamine Biosynthesis Reverses Ca2+ Channel Remodeling in Colon Cancer Cells
Received: 19 December 2018 / Revised: 5 January 2019 / Accepted: 9 January 2019 / Published: 13 January 2019
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Abstract
Store-operated Ca2+ entry (SOCE) is the most important Ca2+ entry pathway in non-excitable cells. Colorectal cancer (CRC) shows decreased Ca2+ store content and enhanced SOCE that correlate with cancer hallmarks and are associated to remodeling of store-operated channels (SOCs). Normal [...] Read more.
Store-operated Ca2+ entry (SOCE) is the most important Ca2+ entry pathway in non-excitable cells. Colorectal cancer (CRC) shows decreased Ca2+ store content and enhanced SOCE that correlate with cancer hallmarks and are associated to remodeling of store-operated channels (SOCs). Normal colonic cells display small, Ca2+-selective currents driven by Orai1 channels. In contrast, CRC cells display larger, non-selective currents driven by Orai1 and transient receptor potential canonical type 1 channels (TRPC1). Difluoromethylornithine (DFMO), a suicide inhibitor of ornithine decarboxylase (ODC), the limiting step in polyamine biosynthesis, strongly prevents CRC, particularly when combined with sulindac. We asked whether DFMO may reverse SOC remodeling in CRC. We found that CRC cells overexpress ODC and treatment with DFMO decreases cancer hallmarks including enhanced cell proliferation and apoptosis resistance. Consistently, DFMO enhances Ca2+ store content and decreases SOCE in CRC cells. Moreover, DFMO abolish selectively the TRPC1-dependent component of SOCs characteristic of CRC cells and this effect is reversed by the polyamine putrescine. Combination of DFMO and sulindac inhibit both SOC components and abolish SOCE in CRC cells. Finally, DFMO treatment inhibits expression of TRPC1 and stromal interaction protein 1 (STIM1) in CRC cells. These results suggest that polyamines contribute to Ca2+ channel remodeling in CRC, and DFMO may prevent CRC by reversing channel remodeling. Full article
(This article belongs to the Special Issue Ion Channels in Cancer)
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Open AccessArticle The Role of the Anti-Aging Protein Klotho in IGF-1 Signaling and Reticular Calcium Leak: Impact on the Chemosensitivity of Dedifferentiated Liposarcomas
Cancers 2018, 10(11), 439; https://doi.org/10.3390/cancers10110439
Received: 22 October 2018 / Accepted: 9 November 2018 / Published: 14 November 2018
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Abstract
By inhibiting Insulin-Like Growth Factor-1-Receptor (IGF-1R) signaling, Klotho (KL) acts like an aging- and tumor-suppressor. We investigated whether KL impacts the aggressiveness of liposarcomas, in which IGF-1R signaling is frequently upregulated. Indeed, we observed that a higher KL expression in liposarcomas is associated [...] Read more.
By inhibiting Insulin-Like Growth Factor-1-Receptor (IGF-1R) signaling, Klotho (KL) acts like an aging- and tumor-suppressor. We investigated whether KL impacts the aggressiveness of liposarcomas, in which IGF-1R signaling is frequently upregulated. Indeed, we observed that a higher KL expression in liposarcomas is associated with a better outcome for patients. Moreover, KL is downregulated in dedifferentiated liposarcomas (DDLPS) compared to well-differentiated tumors and adipose tissue. Because DDLPS are high-grade tumors associated with poor prognosis, we examined the potential of KL as a tool for overcoming therapy resistance. First, we confirmed the attenuation of IGF-1-induced calcium (Ca2+)-response and Extracellular signal-Regulated Kinase 1/2 (ERK1/2) phosphorylation in KL-overexpressing human DDLPS cells. KL overexpression also reduced cell proliferation, clonogenicity, and increased apoptosis induced by gemcitabine, thapsigargin, and ABT-737, all of which are counteracted by IGF-1R-dependent signaling and activate Ca2+-dependent endoplasmic reticulum (ER) stress. Then, we monitored cell death and cytosolic Ca2+-responses and demonstrated that KL increases the reticular Ca2+-leakage by maintaining TRPC6 at the ER and opening the translocon. Only the latter is necessary for sensitizing DDLPS cells to reticular stressors. This was associated with ERK1/2 inhibition and could be mimicked with IGF-1R or MEK inhibitors. These observations provide a new therapeutic strategy in the management of DDLPS. Full article
(This article belongs to the Special Issue Ion Channels in Cancer)
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Open AccessArticle Calcium Independent Effect of Orai1 and STIM1 in Non-Hodgkin B Cell Lymphoma Dissemination
Cancers 2018, 10(11), 402; https://doi.org/10.3390/cancers10110402
Received: 7 September 2018 / Revised: 18 October 2018 / Accepted: 23 October 2018 / Published: 26 October 2018
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Abstract
Ca2+ release-activated Ca2+ channels, composed of Orai1 and STIM1 (stromal interaction molecule 1) proteins, are the main Ca2+ entry mechanism in lymphocytes. Their role in cell migration and metastasis is demonstrated in solid cancers but it remains elusive in malignant [...] Read more.
Ca2+ release-activated Ca2+ channels, composed of Orai1 and STIM1 (stromal interaction molecule 1) proteins, are the main Ca2+ entry mechanism in lymphocytes. Their role in cell migration and metastasis is demonstrated in solid cancers but it remains elusive in malignant hemopathies. Diffuse large B cell lymphoma (DLBCL) is characterized by the dissemination of neoplastic B cells throughout the organism which is under the control of chemokines such as Stromal Derived Factor 1 (SDF-1) and its receptor CXCR4. CXCR4 activation triggers a complex intracellular signaling including an increase in intracellular Ca2+ concentration whose role is still unclear. Using pharmacological and genetic approaches, we revealed that STIM1 and Orai1 were responsible for Ca2+ influx induced by SDF-1. Furthermore, we provide in vitro and in vivo evidence that they are necessary for basal or SDF-1-induced DLBCL cell migration which is independent of Ca2+ entry. We identify that they act as effectors coupling RhoA and ROCK dependent signaling pathway to MLC2 phosphorylation and actin polymerization. Finally, we revealed an alteration of Orai1 and STIM1 expression in extra-nodal DLBCL. Thus, we discovered a novel Ca2+-independent but Orai1 and STIM1-dependent signaling pathway involved in basal and CXCR4 dependent cell migration, which could be relevant for DLBCL physiopathology. Full article
(This article belongs to the Special Issue Ion Channels in Cancer)
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Open AccessArticle TRPC6 Channels Are Required for Proliferation, Migration and Invasion of Breast Cancer Cell Lines by Modulation of Orai1 and Orai3 Surface Exposure
Cancers 2018, 10(9), 331; https://doi.org/10.3390/cancers10090331
Received: 5 August 2018 / Revised: 7 September 2018 / Accepted: 13 September 2018 / Published: 14 September 2018
Cited by 3 | PDF Full-text (4315 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Transient receptor potential channels convey signaling information from a number of stimuli to a wide variety of cellular functions, mainly by inducing changes in cytosolic Ca2+ concentration. Different members of the TRPC, TRPM and TRPV subfamilies have been reported to play a [...] Read more.
Transient receptor potential channels convey signaling information from a number of stimuli to a wide variety of cellular functions, mainly by inducing changes in cytosolic Ca2+ concentration. Different members of the TRPC, TRPM and TRPV subfamilies have been reported to play a role in tumorigenesis. Here we show that the estrogen receptor positive and triple negative breast cancer cell lines, MCF7 and MDA-MB-231, respectively, exhibit enhanced expression of the TRPC6 channel as compared to the non-tumoral MCF10A cell line. In vitro TRPC6 knockdown using shRNA impaired MCF7 and MDA-MB-231 cell proliferation, migration and invasion detected by BrdU incorporation, wound healing and Boyden chamber assays, respectively. Using RNAi-mediated TRPC6 silencing as well as overexpression of the pore-dead dominant-negative TRPC6 mutant we have found that TRPC6 plays a relevant role in the activation of store-operated Ca2+ entry in the breast cancer cell lines but not in non-tumoral breast cells. Finally, we have found that TRPC6 interacts with Orai1 and Orai3 in MCF7 and MDA-MB-231 cells and is required for the translocation of Orai1 and Orai3 to the plasma membrane in MDA-MB-231 and MCF7 cells, respectively, upon Ca2+ store depletion. These findings introduce a novel mechanism for the modulation of Ca2+ influx and the development of different cancer hallmarks in breast cancer cells. Full article
(This article belongs to the Special Issue Ion Channels in Cancer)
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Review

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Open AccessReview Contribution of Anoctamins to Cell Survival and Cell Death
Cancers 2019, 11(3), 382; https://doi.org/10.3390/cancers11030382
Received: 19 February 2019 / Revised: 13 March 2019 / Accepted: 16 March 2019 / Published: 19 March 2019
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Abstract
Before anoctamins (TMEM16 proteins) were identified as a family of Ca2+-activated chloride channels and phospholipid scramblases, the founding member anoctamin 1 (ANO1, TMEM16A) was known as DOG1, a marker protein for gastrointestinal stromal tumors (GIST). Meanwhile, ANO1 has been examined in [...] Read more.
Before anoctamins (TMEM16 proteins) were identified as a family of Ca2+-activated chloride channels and phospholipid scramblases, the founding member anoctamin 1 (ANO1, TMEM16A) was known as DOG1, a marker protein for gastrointestinal stromal tumors (GIST). Meanwhile, ANO1 has been examined in more detail, and the role of ANO1 in cell proliferation and the development of different types of malignomas is now well established. While ANO5, ANO7, and ANO9 may also be relevant for growth of cancers, evidence has been provided for a role of ANO6 (TMEM16F) in regulated cell death. The cellular mechanisms by which anoctamins control cell proliferation and cell death, respectively, are just emerging; however, the pronounced effects of anoctamins on intracellular Ca2+ levels are likely to play a significant role. Recent results suggest that some anoctamins control membrane exocytosis by setting Ca2+i levels near the plasma membrane, and/or by controlling the intracellular Cl concentration. Exocytosis and increased membrane trafficking induced by ANO1 and ANO6 may enhance membrane expression of other chloride channels, such as CFTR and volume activated chloride channels (VRAC). Notably, ANO6-induced phospholipid scrambling with exposure of phosphatidylserine is pivotal for the sheddase function of disintegrin and metalloproteinase (ADAM). This may support cell death and tumorigenic activity of IL-6 by inducing IL-6 trans-signaling. The reported anticancer effects of the anthelminthic drug niclosamide are probably related to the potent inhibitory effect on ANO1, apart from inducing cell cycle arrest through the Let-7d/CDC34 axis. On the contrary, pronounced activation of ANO6 due to a large increase in intracellular calcium, activation of phospholipase A2 or lipid peroxidation, can lead to ferroptotic death of cancer cells. It therefore appears reasonable to search for both inhibitors and potent activators of TMEM16 in order to interfere with cancer growth and metastasis. Full article
(This article belongs to the Special Issue Ion Channels in Cancer)
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Open AccessReview Ion Channels: New Actors Playing in Chemotherapeutic Resistance
Cancers 2019, 11(3), 376; https://doi.org/10.3390/cancers11030376
Received: 1 February 2019 / Revised: 7 March 2019 / Accepted: 12 March 2019 / Published: 16 March 2019
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Abstract
In the battle against cancer cells, therapeutic modalities are drastically limited by intrinsic or acquired drug resistance. Resistance to therapy is not only common, but expected: if systemic agents used for cancer treatment are usually active at the beginning of therapy (i.e., 90% [...] Read more.
In the battle against cancer cells, therapeutic modalities are drastically limited by intrinsic or acquired drug resistance. Resistance to therapy is not only common, but expected: if systemic agents used for cancer treatment are usually active at the beginning of therapy (i.e., 90% of primary breast cancers and 50% of metastases), about 30% of patients with early-stage breast cancer will have recurrent disease. Altered expression of ion channels is now considered as one of the hallmarks of cancer, and several ion channels have been linked to cancer cell resistance. While ion channels have been associated with cell death, apoptosis and even chemoresistance since the late 80s, the molecular mechanisms linking ion channel expression and/or function with chemotherapy have mostly emerged in the last ten years. In this review, we will highlight the relationships between ion channels and resistance to chemotherapy, with a special emphasis on the underlying molecular mechanisms. Full article
(This article belongs to the Special Issue Ion Channels in Cancer)
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Open AccessReview The Transient Receptor Potential Vanilloid Type-2 (TRPV2) Ion Channels in Neurogenesis and Gliomagenesis: Cross-Talk between Transcription Factors and Signaling Molecules
Cancers 2019, 11(3), 322; https://doi.org/10.3390/cancers11030322
Received: 2 February 2019 / Revised: 27 February 2019 / Accepted: 1 March 2019 / Published: 6 March 2019
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Abstract
Recently, the finding of cancer stem cells in brain tumors has increased the possibilities
for advancing new therapeutic approaches with the aim to overcome the limits of current available
treatments. In addition, a role for ion channels, particularly of TRP channels, in developing [...] Read more.
Recently, the finding of cancer stem cells in brain tumors has increased the possibilities
for advancing new therapeutic approaches with the aim to overcome the limits of current available
treatments. In addition, a role for ion channels, particularly of TRP channels, in developing neurons
as well as in brain cancer development and progression have been demonstrated. Herein, we focus
on the latest advancements in understanding the role of TRPV2, a Ca2+ permeable channel belonging
to the TRPV subfamily in neurogenesis and gliomagenesis. TRPV2 has been found to be expressed
in both neural progenitor cells and glioblastoma stem/progenitor-like cells (GSCs). In developing
neurons, post-translational modifications of TRPV2 (e.g., phosphorylation by ERK2) are required to
stimulate Ca2+ signaling and nerve growth factor-mediated neurite outgrowth. TRPV2
overexpression also promotes GSC differentiation and reduces gliomagenesis in vitro and in vivo.
In glioblastoma, TRPV2 inhibits survival and proliferation, and induces Fas/CD95-dependent
apoptosis. Furthermore, by proteomic analysis, the identification of a TRPV2 interactome-based
signature and its relation to glioblastoma progression/recurrence, high or low overall survival and
drug resistance strongly suggest an important role of the TRPV2 channel as a potential biomarker
in glioblastoma prognosis and therapy. Full article
(This article belongs to the Special Issue Ion Channels in Cancer)
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Open AccessReview The Volume-Regulated Anion Channel in Glioblastoma
Cancers 2019, 11(3), 307; https://doi.org/10.3390/cancers11030307
Received: 17 January 2019 / Revised: 22 February 2019 / Accepted: 26 February 2019 / Published: 5 March 2019
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Abstract
Malignancy of glioblastoma multiforme (GBM), the most common and aggressive form of human brain tumor, strongly depends on its enhanced cell invasion and death evasion which make surgery and accompanying therapies highly ineffective. Several ion channels that regulate membrane potential, cytosolic Ca2+ [...] Read more.
Malignancy of glioblastoma multiforme (GBM), the most common and aggressive form of human brain tumor, strongly depends on its enhanced cell invasion and death evasion which make surgery and accompanying therapies highly ineffective. Several ion channels that regulate membrane potential, cytosolic Ca2+ concentration and cell volume in GBM cells play significant roles in sustaining these processes. Among them, the volume-regulated anion channel (VRAC), which mediates the swelling-activated chloride current (IClswell) and is highly expressed in GBM cells, arguably plays a major role. VRAC is primarily involved in reestablishing the original cell volume that may be lost under several physiopathological conditions, but also in sustaining the shape and cell volume changes needed for cell migration and proliferation. While experimentally VRAC is activated by exposing cells to hypotonic solutions that cause the increase of cell volume, in vivo it is thought to be controlled by several different stimuli and modulators. In this review we focus on our recent work showing that two conditions normally occurring in pathological GBM tissues, namely high serum levels and severe hypoxia, were both able to activate VRAC, and their activation was found to promote cell migration and resistance to cell death, both features enhancing GBM malignancy. Also, the fact that the signal transduction pathway leading to VRAC activation appears to involve GBM specific intracellular components, such as diacylglicerol kinase and phosphatidic acid, reportedly not involved in the activation of VRAC in healthy tissues, is a relevant finding. Based on these observations and the impact of VRAC in the physiopathology of GBM, targeting this channel or its intracellular regulators may represent an effective strategy to contrast this lethal tumor. Full article
(This article belongs to the Special Issue Ion Channels in Cancer)
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Open AccessReview Implication of Voltage-Gated Potassium Channels in Neoplastic Cell Proliferation
Cancers 2019, 11(3), 287; https://doi.org/10.3390/cancers11030287
Received: 26 January 2019 / Revised: 21 February 2019 / Accepted: 24 February 2019 / Published: 1 March 2019
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Abstract
Voltage-gated potassium channels (Kv) are the largest group of ion channels. Kv are involved in controlling the resting potential and action potential duration in the heart and brain. Additionally, these proteins participate in cell cycle progression as well as in several other important [...] Read more.
Voltage-gated potassium channels (Kv) are the largest group of ion channels. Kv are involved in controlling the resting potential and action potential duration in the heart and brain. Additionally, these proteins participate in cell cycle progression as well as in several other important features in mammalian cell physiology, such as activation, differentiation, apoptosis, and cell volume control. Therefore, Kv remarkably participate in the cell function by balancing responses. The implication of Kv in physiological and pathophysiological cell growth is the subject of study, as Kv are proposed as therapeutic targets for tumor regression. Though it is widely accepted that Kv channels control proliferation by allowing cell cycle progression, their role is controversial. Kv expression is altered in many cancers, and their participation, as well as their use as tumor markers, is worthy of effort. There is an ever-growing list of Kv that remodel during tumorigenesis. This review focuses on the actual knowledge of Kv channel expression and their relationship with neoplastic proliferation. In this work, we provide an update of what is currently known about these proteins, thereby paving the way for a more precise understanding of the participation of Kv during cancer development. Full article
(This article belongs to the Special Issue Ion Channels in Cancer)
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Open AccessReview Calcium Signaling in Brain Cancers: Roles and Therapeutic Targeting
Cancers 2019, 11(2), 145; https://doi.org/10.3390/cancers11020145
Received: 21 December 2018 / Revised: 22 January 2019 / Accepted: 23 January 2019 / Published: 26 January 2019
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Abstract
Calcium signaling, in addition to its numerous physiological roles, is also implicated in several pathological conditions including cancer. An increasing body of evidence suggest critical roles of calcium signaling in the promotion of different aspects of cancer, including cell proliferation, therapy resistance and [...] Read more.
Calcium signaling, in addition to its numerous physiological roles, is also implicated in several pathological conditions including cancer. An increasing body of evidence suggest critical roles of calcium signaling in the promotion of different aspects of cancer, including cell proliferation, therapy resistance and metastatic-related processes. In many cases, this is associated with altered expression and/or activity of some calcium channels and pumps. Brain cancers have also been the subject of many of these studies. In addition to diverse roles of calcium signals in normal brain function, a number of proteins involved in calcium transport are implicated to have specific roles in some brain cancers including gliomas, medulloblastoma, neuroblastoma and meningioma. This review discusses research that has been conducted so far to understand diverse roles of Ca2+-transporting proteins in the progression of brain cancers, as well as any attempts to target these proteins towards a therapeutic approach for the control of brain cancers. Finally, some knowledge gaps in the field that may need to be further considered are also discussed. Full article
(This article belongs to the Special Issue Ion Channels in Cancer)
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Open AccessReview T-type Calcium Channels in Cancer
Cancers 2019, 11(2), 134; https://doi.org/10.3390/cancers11020134
Received: 10 December 2018 / Revised: 10 January 2019 / Accepted: 17 January 2019 / Published: 23 January 2019
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Abstract
Although voltage-activated Ca2+ channels are a common feature in excitable cells, their expression in cancer tissue is less understood. T-type Ca2+ channels are particularly overexpressed in various cancers. Because of their activation profile at membrane potentials close to rest and the [...] Read more.
Although voltage-activated Ca2+ channels are a common feature in excitable cells, their expression in cancer tissue is less understood. T-type Ca2+ channels are particularly overexpressed in various cancers. Because of their activation profile at membrane potentials close to rest and the generation of a window current, T-type Ca2+ channels may regulate a variety of Ca2+-dependent cellular processes, including cell proliferation, survival, and differentiation. The expression of T-type Ca2+ channels is of special interest as a target for therapeutic interventions. Full article
(This article belongs to the Special Issue Ion Channels in Cancer)
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Open AccessReview Cancer-Associated Intermediate Conductance Ca2+-Activated K+ Channel KCa3.1
Cancers 2019, 11(1), 109; https://doi.org/10.3390/cancers11010109
Received: 14 December 2018 / Revised: 10 January 2019 / Accepted: 13 January 2019 / Published: 17 January 2019
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Abstract
Several tumor entities have been reported to overexpress KCa3.1 potassium channels due to epigenetic, transcriptional, or post-translational modifications. By modulating membrane potential, cell volume, or Ca2+ signaling, KCa3.1 has been proposed to exert pivotal oncogenic functions in tumorigenesis, [...] Read more.
Several tumor entities have been reported to overexpress KCa3.1 potassium channels due to epigenetic, transcriptional, or post-translational modifications. By modulating membrane potential, cell volume, or Ca2+ signaling, KCa3.1 has been proposed to exert pivotal oncogenic functions in tumorigenesis, malignant progression, metastasis, and therapy resistance. Moreover, KCa3.1 is expressed by tumor-promoting stroma cells such as fibroblasts and the tumor vasculature suggesting a role of KCa3.1 in the adaptation of the tumor microenvironment. Combined, this features KCa3.1 as a candidate target for innovative anti-cancer therapy. However, immune cells also express KCa3.1 thereby contributing to T cell activation. Thus, any strategy targeting KCa3.1 in anti-cancer therapy may also modulate anti-tumor immune activity and/or immunosuppression. The present review article highlights the potential of KCa3.1 as an anti-tumor target providing an overview of the current knowledge on its function in tumor pathogenesis with emphasis on vasculo- and angiogenesis as well as anti-cancer immune responses. Full article
(This article belongs to the Special Issue Ion Channels in Cancer)
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Open AccessReview Endolysosomal Ca2+ Signalling and Cancer Hallmarks: Two-Pore Channels on the Move, TRPML1 Lags Behind!
Received: 6 December 2018 / Revised: 21 December 2018 / Accepted: 21 December 2018 / Published: 27 December 2018
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Abstract
The acidic vesicles of the endolysosomal (EL) system are emerging as an intracellular Ca2+ store implicated in the regulation of multiple cellular functions. The EL Ca2+ store releases Ca2+ through a variety of Ca2+-permeable channels, including Transient Receptor [...] Read more.
The acidic vesicles of the endolysosomal (EL) system are emerging as an intracellular Ca2+ store implicated in the regulation of multiple cellular functions. The EL Ca2+ store releases Ca2+ through a variety of Ca2+-permeable channels, including Transient Receptor Potential (TRP) Mucolipin 1-3 (TRPML1-3) and two-pore channels 1-2 (TPC1-2), whereas EL Ca2+ refilling is sustained by the proton gradient across the EL membrane and/or by the endoplasmic reticulum (ER). EL Ca2+ signals may be either spatially restricted to control vesicle trafficking, autophagy and membrane repair or may be amplified into a global Ca2+ signal through the Ca2+-dependent recruitment of ER-embedded channels. Emerging evidence suggested that nicotinic acid adenine dinucleotide phosphate (NAADP)-gated TPCs sustain multiple cancer hallmarks, such as migration, invasiveness and angiogenesis. Herein, we first survey the EL Ca2+ refilling and release mechanisms and then focus on the oncogenic role of EL Ca2+ signaling. While the evidence in favor of TRPML1 involvement in neoplastic transformation is yet to be clearly provided, TPCs are emerging as an alternative target for anticancer therapies. Full article
(This article belongs to the Special Issue Ion Channels in Cancer)
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