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Ion Channels and Transporters: The New Targets for Cancer

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 11703

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Special Issue Editors

Prof. Dr. Alessandra Fiorio Pla

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Guest Editor

1. Laboratory of Cellular and Molecular Angiogenesis, Department of Life Science and Systems Biology, University of Torino, 10123 Turin, Italy
2. Inserm, U1003 - PHYCEL (Physiologie Cellulaire), Université de Lille, 59000 Lille, France
3. Laboratory of Excellence, Ion Channels Science and Therapeutics, Université de Lille, F-59655 Villeneuve d'Ascq, France
Interests: Ca2+ signals and signal transduction pathways; TRP channels; SOC channels; cancer cell migration and adhesion processes; angiogenesis.

Dr. Elena Lastraioli

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Guest Editor

Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence, Viale GB Morgagni, 50134 Firenze, Italy
Interests: cancer; molecular biology; genetics; histology; Liquid Biopsy; ion channels
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Special Issue Information

Dear Colleagues,

Mounting evidence gathered in recent decades has demonstrated that ion channels and transporters (ICT) are aberrantly expressed in several types of human cancers and are considered major players in different aspects of cancer cell behavior. Interestingly, although most of the best-characterized roles played by ICT rely on their channel/transporter activity, there is growing evidence of pathways that underlie the interaction of ICT with different partner proteins, extending interest in ICTs beyond the field of ion channels. Moreover, since they are located on the cell membrane, ICTs represent potential targets to be exploited for diagnostic and therapeutic purposes.

Indeed, a new concept in oncological research has been developed and promoted over the last decade, paving the way to a new chapter of oncology coined ‘Oncochannelopathies’.

In this Special Issue, both research and review articles focusing on ion channel relevance in human tumor are welcomed. Special emphasis should be directed to their potential use in the clinical setting as biomarkers and targets for therapy.

Prof. Dr. Alessandra Fiorio Pla
Dr. Elena Lastraioli
Guest Editors

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Keywords

ion channels
transporters
cancer therapy
biomarkers
human tumors

Published Papers (6 papers)

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Research

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24 pages, 12168 KiB

Open AccessArticle

The Voltage-Gated Hv1 H⁺ Channel Is Expressed in Tumor-Infiltrating Myeloid-Derived Suppressor Cells

by Marco Cozzolino, Adrienn Gyöngyösi, Eva Korpos, Peter Gogolak, Muhammad Umair Naseem, Judit Kállai, Arpad Lanyi and Gyorgy Panyi

Int. J. Mol. Sci. 2023, 24(7), 6216; https://doi.org/10.3390/ijms24076216 - 25 Mar 2023

Cited by 3 | Viewed by 1519

Abstract

Myeloid-derived suppressor cells (MDSCs) are key determinants of the immunosuppressive microenvironment in tumors. As ion channels play key roles in the physiology/pathophysiology of immune cells, we aimed at studying the ion channel repertoire in tumor-derived polymorphonuclear (PMN-MDSC) and monocytic (Mo-MDSC) MDSCs. Subcutaneous tumors in mice were induced by the Lewis lung carcinoma cell line (LLC). The presence of PMN-MDSC (CD11b⁺/Ly6G⁺) and Mo-MDSCs (CD11b⁺/Ly6C⁺) in the tumor tissue was confirmed using immunofluorescence microscopy and cells were identified as CD11b⁺/Ly6G⁺ PMN-MDSCs and CD11b⁺/Ly6C⁺/F4/80⁻/MHCII⁻ Mo-MDSCs using flow cytometry and sorting. The majority of the myeloid cells infiltrating the LLC tumors were PMN-MDSC (~60%) as compared to ~10% being Mo-MDSCs. We showed that PMN- and Mo-MDSCs express the Hv1 H⁺ channel both at the mRNA and at the protein level and that the biophysical and pharmacological properties of the whole-cell currents recapitulate the hallmarks of Hv1 currents: ~40 mV shift in the activation threshold of the current per unit change in the extracellular pH, high H⁺ selectivity, and sensitivity to the Hv1 inhibitor ClGBI. As MDSCs exert immunosuppression mainly by producing reactive oxygen species which is coupled to Hv1-mediated H⁺ currents, Hv1 might be an attractive target for inhibition of MDSCs in tumors. Full article

(This article belongs to the Special Issue Ion Channels and Transporters: The New Targets for Cancer)

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18 pages, 3275 KiB

Open AccessArticle

A Novel Anti-TRPV6 Antibody and Its Application in Cancer Diagnosis In Vitro

by Aurélien Haustrate, Adriana Mihalache, Clément Cordier, Pierre Gosset, Natalia Prevarskaya and V’yacheslav Lehen’kyi

Int. J. Mol. Sci. 2023, 24(1), 419; https://doi.org/10.3390/ijms24010419 - 27 Dec 2022

Cited by 6 | Viewed by 1683

Abstract

Though the first discovery of TRPV6 channel expression in various tissues took place in the early 2000s, reliable tools for its protein detection in various cells and tissues are still missing. Here we show the generation and validation of rabbit polyclonal anti-TRPV6 channel antibodies (rb79–82) against four epitopes of 15 amino acids. Among them, only one antibody, rb79, was capable of detecting the full-length glycosylated form of the TRPV6 channel at around 100 kDa. The generated antibody was shown to be suitable for all in vitro applications, such as immunoblotting, immunoprecipitation, immunocytochemistry, immunofluorescence, etc. One of the most important applications is immunohistochemistry using the paraffin-embedded sections from cancer resection specimens. Using prostate cancer resection specimens, we have confirmed the absence of the TRPV6 protein in both healthy and benign hyperplasia, as well as its expression and correlation to the prostate cancer grades. Thus, the generated rabbit polyclonal anti-TRPV6 channel antibody rb79 is suitable for all in vitro diagnostic applications and particularly for the diagnosis in clinics using paraffin-embedded sections from patients suffering from various diseases and disorders involving the TRPV6 channel. Full article

(This article belongs to the Special Issue Ion Channels and Transporters: The New Targets for Cancer)

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18 pages, 2238 KiB

Open AccessArticle

Prognostic role of hERG1 Potassium Channels in Neuroendocrine Tumours of the Ileum and Pancreas

by Jessica Iorio, Lorenzo Antonuzzo, Emanuela Scarpi, Massimo D’Amico, Claudia Duranti, Luca Messerini, Clotilde Sparano, Damiano Caputo, Daniele Lavacchi, Domenico Borzomati, Alice Antonelli, Lorenzo Nibid, Giuseppe Perrone, Alessandro Coppola, Roberto Coppola, Francesco di Costanzo, Elena Lastraioli and Annarosa Arcangeli

Int. J. Mol. Sci. 2022, 23(18), 10623; https://doi.org/10.3390/ijms231810623 - 13 Sep 2022

Cited by 5 | Viewed by 1724

Abstract

hERG1 potassium channels are widely expressed in human cancers of different origins, where they affect several key aspects of cellular behaviour. The present study was designed to evaluate the expression and clinical relevance of hERG1 protein in cancer tissues from patients suffering from neuroendocrine tumours (NETs) of ileal (iNETs) and pancreatic (pNETs) origin, with available clinicopathological history and follow-up. The study was carried out by immunohistochemistry with an anti-hERG1 monoclonal antibody. In a subset of samples, a different antibody directed against the hERG1/β1 integrin complex was also used. The analysis showed for the first time that hERG1 is expressed in human NETs originating from either the ileum or the pancreas. hERG1 turned out to have a prognostic value in NETs, showing (i) a statistically significant positive impact on OS of patients affected by ileal NETs, regardless the TNM stage; (ii) a statistically significant positive impact on OS of patients affected by aggressive (TNM stage IV) disease, either ileal or pancreatic; (iii) a trend to a negative impact on OS of patients affected by less aggressive (TNM stage I-III) disease, either ileal or pancreatic. Moreover, in order to evaluate whether ERG1 was functionally expressed in a cellular model of pNET, the INS1E rat insulinoma cell line was used, and it emerged that blocking ERG1 with a specific inhibitor of the channel (E4031) turned out in a significant reduction in cell proliferation. Full article

(This article belongs to the Special Issue Ion Channels and Transporters: The New Targets for Cancer)

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19 pages, 4576 KiB

Open AccessArticle

The hEag1 K⁺ Channel Inhibitor Astemizole Stimulates Ca²⁺ Deposition in SaOS-2 and MG-63 Osteosarcoma Cultures

by Beáta Mészáros, Agota Csoti, Tibor G. Szanto, Andrea Telek, Katalin Kovács, Agnes Toth, Julianna Volkó and Gyorgy Panyi

Int. J. Mol. Sci. 2022, 23(18), 10533; https://doi.org/10.3390/ijms231810533 - 11 Sep 2022

Viewed by 1946

Abstract

The hEag1 (Kv10.1) K⁺ channel is normally found in the brain, but it is ectopically expressed in tumor cells, including osteosarcoma. Based on the pivotal role of ion channels in osteogenesis, we tested whether pharmacological modulation of hEag1 may affect osteogenic differentiation of osteosarcoma cell lines. Using molecular biology (RT-PCR), electrophysiology (patch-clamp) and pharmacology (astemizole sensitivity, IC₅₀ = 0.135 μM) we demonstrated that SaOS-2 osteosarcoma cells also express hEag1 channels. SaOS-2 cells also express to KCa1.1 K⁺ channels as shown by mRNA expression and paxilline sensitivity of the current. The inhibition of hEag1 (2 μM astemizole) or KCa1.1 (1 mM TEA) alone did not induce Ca²⁺ deposition in SaOS-2 cultures, however, these inhibitors, at identical concentrations, increased Ca²⁺ deposition evoked by the classical or pathological (inorganic phosphate, Pi) induction pathway without causing cytotoxicity, as reported by three completer assays (LDH release, MTT assay and SRB protein assay). We observed a similar effect of astemizole on Ca²⁺ deposition in MG-63 osteosarcoma cultures as well. We propose that the increase in the osteogenic stimuli-induced mineral matrix formation of osteosarcoma cell lines by inhibiting hEag1 may be a useful tool to drive terminal differentiation of osteosarcoma. Full article

(This article belongs to the Special Issue Ion Channels and Transporters: The New Targets for Cancer)

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20 pages, 2918 KiB

Open AccessArticle

The TRPC1 Channel Forms a PI3K/CaM Complex and Regulates Pancreatic Ductal Adenocarcinoma Cell Proliferation in a Ca²⁺-Independent Manner

by Julie Schnipper, Sana Kouba, Frédéric Hague, Alban Girault, Pierre Rybarczyk, Marie-Sophie Telliez, Stéphanie Guénin, Riad Tebbakha, Henri Sevestre, Ahmed Ahidouch, Stine Falsig Pedersen and Halima Ouadid-Ahidouch

Int. J. Mol. Sci. 2022, 23(14), 7923; https://doi.org/10.3390/ijms23147923 - 18 Jul 2022

Cited by 2 | Viewed by 1638

Abstract

Dysregulation of the transient receptor canonical ion channel (TRPC1) has been found in several cancer types, yet the underlying molecular mechanisms through which TRPC1 impacts pancreatic ductal adenocarcinoma (PDAC) cell proliferation are incompletely understood. Here, we found that TRPC1 is upregulated in human PDAC tissue compared to adjacent pancreatic tissue and this higher expression correlates with low overall survival. TRPC1 is, as well, upregulated in the aggressive PDAC cell line PANC-1, compared to a duct-like cell line, and its knockdown (KD) reduced cell proliferation along with PANC-1 3D spheroid growth by arresting cells in the G1/S phase whilst decreasing cyclin A, CDK2, CDK6, and increasing p21^CIP1 expression. In addition, the KD of TRPC1 neither affected Ca²⁺ influx nor store-operated Ca²⁺ entry (SOCE) and reduced cell proliferation independently of extracellular calcium. Interestingly, TRPC1 interacted with the PI3K-p85α subunit and calmodulin (CaM); both the CaM protein level and AKT phosphorylation were reduced upon TRPC1 KD. In conclusion, our results show that TRPC1 regulates PDAC cell proliferation and cell cycle progression by interacting with PI3K-p85α and CaM through a Ca²⁺-independent pathway. Full article

(This article belongs to the Special Issue Ion Channels and Transporters: The New Targets for Cancer)

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Review

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23 pages, 1437 KiB

Open AccessReview

Crosstalk between Ca²⁺ Signaling and Cancer Stemness: The Link to Cisplatin Resistance

by Sana Kouba, Frédéric Hague, Ahmed Ahidouch and Halima Ouadid-Ahidouch

Int. J. Mol. Sci. 2022, 23(18), 10687; https://doi.org/10.3390/ijms231810687 - 14 Sep 2022

Cited by 4 | Viewed by 2435

Abstract

In the fight against cancer, therapeutic strategies using cisplatin are severely limited by the appearance of a resistant phenotype. While cisplatin is usually efficient at the beginning of the treatment, several patients endure resistance to this agent and face relapse. One of the reasons for this resistant phenotype is the emergence of a cell subpopulation known as cancer stem cells (CSCs). Due to their quiescent phenotype and self-renewal abilities, these cells have recently been recognized as a crucial field of investigation in cancer and treatment resistance. Changes in intracellular calcium (Ca²⁺) through Ca²⁺ channel activity are essential for many cellular processes such as proliferation, migration, differentiation, and survival in various cell types. It is now proved that altered Ca²⁺ signaling is a hallmark of cancer, and several Ca²⁺ channels have been linked to CSC functions and therapy resistance. Moreover, cisplatin was shown to interfere with Ca²⁺ homeostasis; thus, it is considered likely that cisplatin-induced aberrant Ca²⁺ signaling is linked to CSCs biology and, therefore, therapy failure. The molecular signature defining the resistant phenotype varies between tumors, and the number of resistance mechanisms activated in response to a range of pressures dictates the global degree of cisplatin resistance. However, if we can understand the molecular mechanisms linking Ca²⁺ to cisplatin-induced resistance and CSC behaviors, alternative and novel therapeutic strategies could be considered. In this review, we examine how cisplatin interferes with Ca²⁺ homeostasis in tumor cells. We also summarize how cisplatin induces CSC markers in cancer. Finally, we highlight the role of Ca²⁺ in cancer stemness and focus on how they are involved in cisplatin-induced resistance through the increase of cancer stem cell populations and via specific pathways. Full article

(This article belongs to the Special Issue Ion Channels and Transporters: The New Targets for Cancer)

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