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Cancers
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The Emerging Role of Ion Channels in Cancer Treatment
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The Emerging Role of Ion Channels in Cancer Treatment

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: 31 January 2025 | Viewed by 8238

Special Issue Editor

Dr. V'yacheslav Lehen'kyi

E-Mail Website
Guest Editor
Laboratory of Cell Physiology, INSERM U1003, Laboratory of Excellence Ion Channels Science and Therapeutics, Department of Biology, Faculty of Science and Technologies, University of Lille, 59650 Villeneuve d'Ascq, France
Interests: ion channels; calcium; TRPV6; tumor targeting in vivo; innovative therapy

Special Issue Information

Dear Colleagues,

A considerable amount of evidence has been demonstrated to date regarding the role of ion channels in all essential processes of carcinogenesis, including cell proliferation, apoptosis resistance, migration, invasion, angiogenesis, etc. In fact, ion signaling is strongly involved in the vast majority, if not in all, of the cell regulation processes, both normal and pathophysiological. Thus, targeting ion channels represents a prospective treatment, particularly when used in combination with the existing cell-toxic drugs. Recently, it has been demonstrated that ion channels may be involved in anti-cancer drug resistance, and thus their targeting would provide a benefit for patients, especially in the framework of precision therapy.

The focus of this Special Issue is thus to consider ion channel regulation as well as downstream signaling in cancer treatment and drug resistance.

Dr. V'yacheslav Lehen'kyi
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 submissions that pass pre-check are 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 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 semimonthly 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 2900 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

  • ion channels
  • ion signaling
  • tumor targeting
  • cancer treatment
  • therapy resistance
  • precision therapy

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Published Papers (6 papers)

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Research

Jump to: Review, Other

13 pages, 2066 KiB  
Article
Inhibition of K+ Channels Affects the Target Cell Killing Potential of CAR T Cells
by Ghofrane Medyouni, Orsolya Vörös, Vivien Jusztus, György Panyi, György Vereb, Árpád Szöőr and Péter Hajdu
Cancers 2024, 16(22), 3750; https://doi.org/10.3390/cancers16223750 - 6 Nov 2024
Viewed by 415
Abstract
Ion channels of T cells (Kv1.3, KCa3.1, and CRAC) participate in the regulation of activation and effector functions via modulation of the Ca2+-dependent pathway. T cells expressing chimeric antigen receptors (CAR T cells) showed a remarkable role in anti-tumor therapy, especially [...] Read more.
Ion channels of T cells (Kv1.3, KCa3.1, and CRAC) participate in the regulation of activation and effector functions via modulation of the Ca2+-dependent pathway. T cells expressing chimeric antigen receptors (CAR T cells) showed a remarkable role in anti-tumor therapy, especially in the treatment of chemotherapy-resistant liquid cancers. Nevertheless, many challenges remain to be overcome to improve the treatment for solid tumors. In this study, we assessed the expression and role of ion channels in CAR T cells. We found that HER2-specific CAR T cells had higher KCa3.1 conductance compared to the non-transduced (NT, control) cells, which was more prominent in the CD8+ population (CD4+ cell also showed elevation). Conversely, the Kv1.3 expression level was the same for all cell types (CD4+, CD8+, CAR, and NT). Single-cell Ca2+ imaging revealed that thapsigargin-induced SOCE via CRAC is suppressed in CD8+ CAR T cells, unlike for CD4+ and CD8+ NT cells. To dissect the functional role of Kv1.3 and KCa3.1, we used specific antagonists (Kv1.3: Vm24; KCa3.1: TRAM-34): the target cell elimination capacity of the CD8+ CAR T cells was improved either by blocking KCa3.1 or Kv1.3. These results imply that ion channels could be a target in CAR T cell immunotherapy elaboration. Full article
(This article belongs to the Special Issue The Emerging Role of Ion Channels in Cancer Treatment)
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30 pages, 3287 KiB  
Article
GABA(A) Receptor Activation Drives GABARAP–Nix Mediated Autophagy to Radiation-Sensitize Primary and Brain-Metastatic Lung Adenocarcinoma Tumors
by Debanjan Bhattacharya, Riccardo Barrile, Donatien Kamdem Toukam, Vaibhavkumar S. Gawali, Laura Kallay, Taukir Ahmed, Hawley Brown, Sepideh Rezvanian, Aniruddha Karve, Pankaj B. Desai, Mario Medvedovic, Kyle Wang, Dan Ionascu, Nusrat Harun, Subrahmanya Vallabhapurapu, Chenran Wang, Xiaoyang Qi, Andrew M. Baschnagel, Joshua A. Kritzer, James M. Cook, Daniel A. Pomeranz Krummel and Soma Senguptaadd Show full author list remove Hide full author list
Cancers 2024, 16(18), 3167; https://doi.org/10.3390/cancers16183167 - 15 Sep 2024
Viewed by 2224
Abstract
In non-small cell lung cancer (NSCLC) treatment, radiotherapy responses are not durable and toxicity limits therapy. We find that AM-101, a synthetic benzodiazepine activator of GABA(A) receptor, impairs the viability and clonogenicity of both primary and brain-metastatic NSCLC cells. Employing a human-relevant ex [...] Read more.
In non-small cell lung cancer (NSCLC) treatment, radiotherapy responses are not durable and toxicity limits therapy. We find that AM-101, a synthetic benzodiazepine activator of GABA(A) receptor, impairs the viability and clonogenicity of both primary and brain-metastatic NSCLC cells. Employing a human-relevant ex vivo ‘chip’, AM-101 is as efficacious as docetaxel, a chemotherapeutic used with radiotherapy for advanced-stage NSCLC. In vivo, AM-101 potentiates radiation, including conferring a significant survival benefit to mice bearing NSCLC intracranial tumors generated using a patient-derived metastatic line. GABA(A) receptor activation stimulates a selective-autophagic response via the multimerization of GABA(A) receptor-associated protein, GABARAP, the stabilization of mitochondrial receptor Nix, and the utilization of ubiquitin-binding protein p62. A high-affinity peptide disrupting Nix binding to GABARAP inhibits AM-101 cytotoxicity. This supports a model of GABA(A) receptor activation driving a GABARAP–Nix multimerization axis that triggers autophagy. In patients receiving radiotherapy, GABA(A) receptor activation may improve tumor control while allowing radiation dose de-intensification to reduce toxicity. Full article
(This article belongs to the Special Issue The Emerging Role of Ion Channels in Cancer Treatment)
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15 pages, 5594 KiB  
Article
Extended Synaptotagmins 1 and 2 Are Required for Store-Operated Calcium Entry, Cell Migration and Viability in Breast Cancer Cells
by Pedro C. Redondo, Jose J. Lopez, Sandra Alvarado, Isaac Jardin, Joel Nieto-Felipe, Alvaro Macias-Diaz, Vanesa Jimenez-Velarde, Gines M. Salido and Juan A. Rosado
Cancers 2024, 16(14), 2518; https://doi.org/10.3390/cancers16142518 - 11 Jul 2024
Viewed by 909
Abstract
Extended synaptotagmins (E-Syts) are endoplasmic reticulum (ER)-associated proteins that facilitate the tethering of the ER to the plasma membrane (PM), participating in lipid transfer between the membranes and supporting the Orai1–STIM1 interaction at ER–PM junctions. Orai1 and STIM1 are the core proteins of [...] Read more.
Extended synaptotagmins (E-Syts) are endoplasmic reticulum (ER)-associated proteins that facilitate the tethering of the ER to the plasma membrane (PM), participating in lipid transfer between the membranes and supporting the Orai1–STIM1 interaction at ER–PM junctions. Orai1 and STIM1 are the core proteins of store-operated Ca2+ entry (SOCE), a major mechanism for Ca2+ influx that regulates a variety of cellular functions. Aberrant modulation of SOCE in cells from different types of cancer has been reported to underlie the development of several tumoral features. Here we show that estrogen receptor-positive (ER+) breast cancer MCF7 and T47D cells and triple-negative breast cancer (TNBC) MDA-MB-231 cells overexpress E-Syt1 and E-Syt2 at the protein level; the latter is also overexpressed in the TNBC BT20 cell line. E-Syt1 and E-Syt2 knockdown was without effect on SOCE in non-tumoral MCF10A breast epithelial cells and ER+ T47D breast cancer cells; however, SOCE was significantly attenuated in ER+ MCF7 cells and TNBC MDA-MB-231 and BT20 cells upon transfection with siRNA E-Syt1 or E-Syt2. Consistent with this, E-Syt1 and E-Syt2 knockdown significantly reduced cell migration and viability in ER+ MCF7 cells and the TNBC cells investigated. To summarize, E-Syt1 and E-Syt2 play a relevant functional role in breast cancer cells. Full article
(This article belongs to the Special Issue The Emerging Role of Ion Channels in Cancer Treatment)
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22 pages, 9514 KiB  
Article
TRPV6 Channel Is Involved in Pancreatic Ductal Adenocarcinoma Aggressiveness and Resistance to Chemotherapeutics
by Gonçalo Mesquita, Aurélien Haustrate, Adriana Mihalache, Benjamin Soret, Clément Cordier, Emilie Desruelles, Erika Duval, Zoltan Pethö, Natalia Prevarskaya, Albrecht Schwab and V’yacheslav Lehen’kyi
Cancers 2023, 15(24), 5769; https://doi.org/10.3390/cancers15245769 - 8 Dec 2023
Viewed by 1410
Abstract
Pancreatic ductal adenocarcinoma (PDAC) stands as a highly aggressive and lethal cancer, characterized by a grim prognosis and scarce treatment alternatives. Within this context, TRPV6, a calcium-permeable channel, emerges as a noteworthy candidate due to its overexpression in various cancers, capable of influencing [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) stands as a highly aggressive and lethal cancer, characterized by a grim prognosis and scarce treatment alternatives. Within this context, TRPV6, a calcium-permeable channel, emerges as a noteworthy candidate due to its overexpression in various cancers, capable of influencing the cell behavior in different cancer entities. Nonetheless, the exact expression pattern and functional significance of TRPV6 in the context of PDAC remains enigmatic. This study scrutinizes the expression of TRPV6 in tissue specimens obtained from 46 PDAC patients across distinct stages and grades. We manipulated TRPV6 expression (knockdown, overexpression) in the human PDAC cell lines Panc-1 and Capan-1. Subsequently, we analyzed its impact on multiple facets, encompassing Ca2+ influx, proliferation, apoptosis, migration, chemoresistance, and tumor growth, both in vitro and in vivo. Notably, the data indicate a direct correlation between TRPV6 expression levels, tumor stage, and grade, establishing a link between TRPV6 and PDAC proliferation in tissue samples. Decreasing TRPV6 expression via knockdown hampered Ca2+ influx, resulting in diminished proliferation and viability in both cell lines, and cell cycle progression in Panc-1. The knockdown simultaneously led to an increase in apoptotic rates and increased the susceptibility of cells to 5-FU and gemcitabine treatments. Moreover, it accelerated migration and promoted collective movement among Panc-1 cells. Conversely, TRPV6 overexpression yielded opposing outcomes in terms of proliferation in Panc-1 and Capan-1, and the migration of Panc-1 cells. Intriguingly, both TRPV6 knockdown and overexpression diminished the process of tumor formation in vivo. This intricate interplay suggests that PDAC aggressiveness relies on a fine-tuned TRPV6 expression, raising its profile as a putative therapeutic target. Full article
(This article belongs to the Special Issue The Emerging Role of Ion Channels in Cancer Treatment)
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Review

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16 pages, 1326 KiB  
Review
Phytochemical Modulation of Ion Channels in Oncologic Symptomatology and Treatment
by Rohan Rao, Caroline Mohammed, Lise Alschuler, Daniel A. Pomeranz Krummel and Soma Sengupta
Cancers 2024, 16(9), 1786; https://doi.org/10.3390/cancers16091786 - 6 May 2024
Viewed by 2169
Abstract
Modern chemotherapies offer a broad approach to cancer treatment but eliminate both cancer and non-cancer cells indiscriminately and, thus, are associated with a host of side effects. Advances in precision oncology have brought about new targeted therapeutics, albeit mostly limited to a subset [...] Read more.
Modern chemotherapies offer a broad approach to cancer treatment but eliminate both cancer and non-cancer cells indiscriminately and, thus, are associated with a host of side effects. Advances in precision oncology have brought about new targeted therapeutics, albeit mostly limited to a subset of patients with an actionable mutation. They too come with side effects and, ultimately, ‘self-resistance’ to the treatment. There is recent interest in the modulation of ion channels, transmembrane proteins that regulate the flow of electrically charged molecules in and out of cells, as an approach to aid treatment of cancer. Phytochemicals have been shown to act on ion channels with high specificity regardless of the tumor’s genetic profile. This paper explores the use of phytochemicals in cancer symptom management and treatment. Full article
(This article belongs to the Special Issue The Emerging Role of Ion Channels in Cancer Treatment)
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Other

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10 pages, 880 KiB  
Opinion
Proton-Mediated PIEZO2 Channelopathy: Linking Oxaliplatin Treatment to Impaired Proprioception and Cognitive Deficits
by Balázs Sonkodi
Cancers 2024, 16(23), 3898; https://doi.org/10.3390/cancers16233898 - 21 Nov 2024
Viewed by 288
Abstract
Oxaliplatin induces acute neuropathy within a few hours post-treatment, with symptoms persisting for several days. Delayed onset muscle soreness also causes the delayed onset of mechanical pain sensation starting at about 6–8 h and lasting up to a week after exercise. Both conditions [...] Read more.
Oxaliplatin induces acute neuropathy within a few hours post-treatment, with symptoms persisting for several days. Delayed onset muscle soreness also causes the delayed onset of mechanical pain sensation starting at about 6–8 h and lasting up to a week after exercise. Both conditions come with impaired proprioception and could be chronic if these bouts are repeated frequently. The involvement of PIEZO2 ion channels, as the principal mechanosensory channels responsible for proprioception, is theorized in both conditions as well. The current opinion manuscript is meant to explain how the minor stretch-related microdamage of PIEZO2 on Type Ia proprioceptive terminals could explain the aforementioned symptoms of impaired proprioception. This includes a platinum-induced proton affinity ‘switch’ on these proprioceptive endings with PIEZO2 content, resulting in this being the likely initiating cause. Furthermore, it postulates how the proton-based ultrafast long-range oscillatory synchronization to the hippocampus could be impaired due to this microdamage on Type Ia proprioceptive terminals. Finally, the manuscript provides insight into how the impairment of the PIEZO2-initiated ultrafast muscle–brain axis may contribute to chemobrain and its associated cognitive and memory deficits. Full article
(This article belongs to the Special Issue The Emerging Role of Ion Channels in Cancer Treatment)
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