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Bano N, Parveen S, Saeed M, Siddiqui S, Abohassan M, Mir SS. Drug Repurposing of Selected Antibiotics: An Emerging Approach in Cancer Drug Discovery. ACS OMEGA 2024; 9:26762-26779. [PMID: 38947816 PMCID: PMC11209889 DOI: 10.1021/acsomega.4c00617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 05/19/2024] [Accepted: 05/29/2024] [Indexed: 07/02/2024]
Abstract
Drug repurposing is a method of investigating new therapeutic applications for previously approved medications. This repurposing approach to "old" medications is now highly efficient, simple to arrange, and cost-effective and poses little risk of failure in treating a variety of disorders, including cancer. Drug repurposing for cancer therapy is currently a key topic of study. It is a way of exploring recent therapeutic applications for already-existing drugs. Theoretically, the repurposing strategy has various advantages over the recognized challenges of creating new molecular entities, including being faster, safer, easier, and less expensive. In the real world, several medications have been repurposed, including aspirin, metformin, and chloroquine. However, doctors and scientists address numerous challenges when repurposing drugs, such as the fact that most drugs are not cost-effective and are resistant to bacteria. So the goal of this review is to gather information regarding repurposing pharmaceuticals to make them more cost-effective and harder for bacteria to resist. Cancer patients are more susceptible to bacterial infections. Due to their weak immune systems, antibiotics help protect them from a variety of infectious diseases. Although antibiotics are not immune boosters, they do benefit the defense system by killing bacteria and slowing the growth of cancer cells. Their use also increases the therapeutic efficacy and helps avoid recurrence. Of late, antibiotics have been repurposed as potent anticancer agents because of the evolutionary relationship between the prokaryotic genome and mitochondrial DNA of eukaryotes. Anticancer antibiotics that prevent cancer cells from growing by interfering with their DNA and blocking growth of promoters, which include anthracyclines, daunorubicin, epirubicin, mitoxantrone, doxorubicin, and idarubicin, are another type of FDA-approved antibiotics used to treat cancer. According to the endosymbiotic hypothesis, prokaryotes and eukaryotes are thought to have an evolutionary relationship. Hence, in this study, we are trying to explore antibiotics that are necessary for treating diseases, including cancer, helping people reduce deaths associated with various infections, and substantially extending people's life expectancy and quality of life.
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Affiliation(s)
- Nilofer Bano
- Molecular
Cell Biology Laboratory, Integral Centre of Excellence for Interdisciplinary
Research (ICEIR-4), Integral University, Kursi Road, Lucknow 226026, India
- Department
of Bioengineering, Faculty of Engineering, Integral University, Kursi Road, Lucknow 226026, India
| | - Sana Parveen
- Molecular
Cell Biology Laboratory, Integral Centre of Excellence for Interdisciplinary
Research (ICEIR-4), Integral University, Kursi Road, Lucknow 226026, India
- Department
of Biosciences, Faculty of Science, Integral
University, Kursi Road, Lucknow 226026, India
| | - Mohd Saeed
- Department
of Biology, College of Sciences, University
of Hail, P.O. Box 2240, Hail 55476, Saudi Arabia
| | - Samra Siddiqui
- Department
of Health Services Management, College of Public Health and Health
Informatics, University of Hail, Hail 55476, Saudi Arabia
| | - Mohammad Abohassan
- Department
of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha 61421, Saudi Arabia
| | - Snober S. Mir
- Molecular
Cell Biology Laboratory, Integral Centre of Excellence for Interdisciplinary
Research (ICEIR-4), Integral University, Kursi Road, Lucknow 226026, India
- Department
of Biosciences, Faculty of Science, Integral
University, Kursi Road, Lucknow 226026, India
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Arcangeli A, Iorio J, Duranti C. Targeting the hERG1 and β1 integrin complex for cancer treatment. Expert Opin Ther Targets 2024; 28:145-157. [PMID: 38372580 DOI: 10.1080/14728222.2024.2318449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Accepted: 02/09/2024] [Indexed: 02/20/2024]
Abstract
INTRODUCTION Despite great advances, novel therapeutic targets and strategies are still needed, in particular for some carcinomas in the metastatic stage (breast cancer, colorectal cancer, pancreatic ductal adenocarcinoma and the clear cell renal carcinoma). Ion channels may be considered good cancer biomarkers and targets for antineoplastic therapy. These concepts are particularly relevant considering the hERG1 potassium channel as a novel target for antineoplastic therapy. AREAS COVERED A great deal of evidence demonstrates that hERG1 is aberrantly expressed in human cancers, in particular in aggressive carcinomas. A relevant cornerstone was the discovery that, in cancer cells, the channel is present in a very peculiar conformation, strictly bound to the β1 subunit of integrin receptors. The hERG1/β1 integrin complex does not occur in the heart. Starting from this evidence, we developed a novel single chain bispecific antibody (scDb-hERG1-β1), which specifically targets the hERG1/β1 integrin complex and exerts antineoplastic effects in preclinical experiments. EXPERT OPINION Since hERG1 blockade cannot be pursued for antineoplastic therapy due to the severe cardiac toxic effects (ventricular arrhythmias) that many hERG1 blockers exert, different strategies must be identified to specifically target hERG1 in cancer. The targeting of the hERG1/β1 integrin complex through the bispecific antibody scDb-hERG1-β1 can overcome such hindrances.
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Affiliation(s)
- Annarosa Arcangeli
- Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence, Firenze, Italy
- CSDC (Center for the Study of complex dynamics), University of Florence, Sesto Fiorentino (FI), Italy
- MCK Therapeutics srl, Pistoia (PT), Italy
| | - Jessica Iorio
- Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence, Firenze, Italy
| | - Claudia Duranti
- Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence, Firenze, Italy
- MCK Therapeutics srl, Pistoia (PT), Italy
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Duranti C, Iorio J, Bagni G, Chioccioli Altadonna G, Fillion T, Lulli M, D'Alessandro FN, Montalbano A, Lastraioli E, Fanelli D, Coppola S, Schmidt T, Piazza F, Becchetti A, Arcangeli A. Integrins regulate hERG1 dynamics by girdin-dependent Gαi3: signaling and modeling in cancer cells. Life Sci Alliance 2024; 7:e202302135. [PMID: 37923359 PMCID: PMC10624597 DOI: 10.26508/lsa.202302135] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Revised: 10/22/2023] [Accepted: 10/23/2023] [Indexed: 11/07/2023] Open
Abstract
The hERG1 potassium channel is aberrantly over expressed in tumors and regulates the cancer cell response to integrin-dependent adhesion. We unravel a novel signaling pathway by which integrin engagement by the ECM protein fibronectin promotes hERG1 translocation to the plasma membrane and its association with β1 integrins, by activating girdin-dependent Gαi3 proteins and protein kinase B (Akt). By sequestering hERG1, β1 integrins make it avoid Rab5-mediated endocytosis, where unbound channels are degraded. The cycle of hERG1 expression determines the resting potential (Vrest) oscillations and drives the cortical f-actin dynamics and thus cell motility. To interpret the slow biphasic kinetics of hERG1/β1 integrin interplay, we developed a mathematical model based on a generic balanced inactivation-like module. Integrin-mediated cell adhesion triggers two contrary responses: a rapid stimulation of hERG1/β1 complex formation, followed by a slow inhibition which restores the initial condition. The protracted hERG1/β1 integrin cycle determines the slow time course and cyclic behavior of cell migration in cancer cells.
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Affiliation(s)
- Claudia Duranti
- Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence, Florence, Italy
| | - Jessica Iorio
- Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence, Florence, Italy
| | - Giacomo Bagni
- Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence, Florence, Italy
| | - Ginevra Chioccioli Altadonna
- Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence, Florence, Italy
- Department of Medical Biotechnologies, University of Siena, Siena, Italy
| | - Thibault Fillion
- Department of Physics, University of Florence, and Florence Section of INFN, Florence, Italy
- Université d'Orléans and Centre de Biophysique Moléculaire (CBM), CNRS UPR 4301, Orléans, France
| | - Matteo Lulli
- Department of Experimental and Clinical Biochemical Sciences, Section of General Pathology, University of Florence, Florence, Italy
| | - Franco Nicolas D'Alessandro
- Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence, Florence, Italy
- Department of Medical Biotechnologies, University of Siena, Siena, Italy
| | - Alberto Montalbano
- Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence, Florence, Italy
| | - Elena Lastraioli
- Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence, Florence, Italy
- CSDC (Center for the Study of complex dynamics), University of Florence, Florence, Italy
| | - Duccio Fanelli
- Department of Physics, University of Florence, and Florence Section of INFN, Florence, Italy
- CSDC (Center for the Study of complex dynamics), University of Florence, Florence, Italy
| | - Stefano Coppola
- Department of Physics, University of Leiden, Leiden, Netherlands
| | - Thomas Schmidt
- Department of Physics, University of Leiden, Leiden, Netherlands
| | - Francesco Piazza
- Department of Physics, University of Florence, and Florence Section of INFN, Florence, Italy
- Université d'Orléans and Centre de Biophysique Moléculaire (CBM), CNRS UPR 4301, Orléans, France
- CSDC (Center for the Study of complex dynamics), University of Florence, Florence, Italy
| | - Andrea Becchetti
- Department of Biotechnology and Biosciences, University of Milano Bicocca, Milan, Italy
| | - Annarosa Arcangeli
- Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence, Florence, Italy
- CSDC (Center for the Study of complex dynamics), University of Florence, Florence, Italy
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Li Z, Ge H, Xie Y, Zhang Y, Zhao X, Sun W, Song M. Luteolin inhibits angiogenesis and enhances radiotherapy sensitivity of laryngeal cancer via downregulating Integrin β1. Tissue Cell 2023; 85:102235. [PMID: 37826960 DOI: 10.1016/j.tice.2023.102235] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 10/05/2023] [Accepted: 10/05/2023] [Indexed: 10/14/2023]
Abstract
AIM To demonstrate the role and mechanism of luteolin in radio-sensitization and angiogenesis of laryngeal cancer. METHODS Firstly, we analyzed the cytotoxicity of Luteolin and radiation sensitive cytotoxicity through CCK8, and selected subsequent radiation doses and Luteolin concentrations. Next, we further analyzed the effects of Luteolin on radiation sensitivity and neovascularization of laryngeal cancer, and conducted CCK8, plate cloning, and angiogenesis experiments, respectively. At the same time, the effects of individual treatment and combination treatment on the expression of Integrin β1 and VEGFA were analyzed through immunofluorescence analysis. We also analyzed the regulation of Integrin β1 protein expression by Luteolin through Western blot. To investigate the mechanism of Integrin β1, we transfected overexpressed and silenced Integrin β1 vectors and analyzed the role of Integrin β1 in Luteolin enhancing radiation sensitivity of laryngeal cancer by repeating the above experiments. We have also constructed an in vivo subcutaneous tumor transplantation model to further validate the cell experimental results. The expression of Integrin, KI67, VEGFA, and CD31 was analyzed through Western blot and immunohistochemistry experiments. RESULTS Radiation inhibited cell proliferation and decreased Integrin β1 expression, and increased the radiosensitivity through inhibiting cell proliferation, and inhibit angiogenesis during radiation. Overexpression of Integrin β1 weakened radiotherapy sensitivity on the basis of cells treated with combined administration. Integrin β1 is considered as the downstream molecule of luteolin, participating in radiosensitivity of luteolin to FaDu cells. Animal experiments also demonstrated that luteolin strengthened tumor suppression and anti-angiogenesis during radiation via Integrin β1. CONCLUSION In summary, our results manifested that radio-sensitivity effect of luteolin depended on downregulating Integrin β1 in laryngocarcinoma.
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Affiliation(s)
- Zhen Li
- Department of Otorhinolaryngology, Yantaishan Hospital, Yantai, Shandong, China
| | - Hongzhou Ge
- Department of Otorhinolaryngology, Qingdao Traditional Chinese Medicine Hospital (Qingdao Hiser Hospital) Qingdao Hiser Hospital Affiliated of Qingdao University, Qingdao, Shandong, China
| | - Yonggang Xie
- Department of Anesthesiology, The Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, China
| | - Yueqin Zhang
- Department of Otorhinolaryngology, Yantaishan Hospital, Yantai, Shandong, China
| | - Xiaoyan Zhao
- Department of Otorhinolaryngology, Yantaishan Hospital, Yantai, Shandong, China
| | - Wen Sun
- Department of Otorhinolaryngology, Yantaishan Hospital, Yantai, Shandong, China
| | - Meiyan Song
- Administrative Department, Yantaishan Hospital, Yantai, Shandong, China.
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Becchetti A. Interplay of Ca 2+ and K + signals in cell physiology and cancer. CURRENT TOPICS IN MEMBRANES 2023; 92:15-46. [PMID: 38007266 DOI: 10.1016/bs.ctm.2023.09.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/27/2023]
Abstract
The cytoplasmic Ca2+ concentration and the activity of K+ channels on the plasma membrane regulate cellular processes ranging from mitosis to oriented migration. The interplay between Ca2+ and K+ signals is intricate, and different cell types rely on peculiar cellular mechanisms. Derangement of these mechanisms accompanies the neoplastic progression. The calcium signals modulated by voltage-gated (KV) and calcium-dependent (KCa) K+ channel activity regulate progression of the cell division cycle, the release of growth factors, apoptosis, cell motility and migration. Moreover, KV channels regulate the cell response to the local microenvironment by assembling with cell adhesion and growth factor receptors. This chapter summarizes the pathophysiological roles of Ca2+ and K+ fluxes in normal and cancer cells, by concentrating on several biological systems in which these functions have been studied in depth, such as early embryos, mammalian cell lines, T lymphocytes, gliomas and colorectal cancer cells. A full understanding of the underlying mechanisms will offer a comprehensive view of the ion channel implication in cancer biology and suggest potential pharmacological targets for novel therapeutic approaches in oncology.
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Affiliation(s)
- Andrea Becchetti
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milano, Italy.
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Wawrzkiewicz-Jałowiecka A, Lalik A, Lukasiak A, Richter-Laskowska M, Trybek P, Ejfler M, Opałka M, Wardejn S, Delfino DV. Potassium Channels, Glucose Metabolism and Glycosylation in Cancer Cells. Int J Mol Sci 2023; 24:ijms24097942. [PMID: 37175655 PMCID: PMC10178682 DOI: 10.3390/ijms24097942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 04/24/2023] [Accepted: 04/25/2023] [Indexed: 05/15/2023] Open
Abstract
Potassium channels emerge as one of the crucial groups of proteins that shape the biology of cancer cells. Their involvement in processes like cell growth, migration, or electric signaling, seems obvious. However, the relationship between the function of K+ channels, glucose metabolism, and cancer glycome appears much more intriguing. Among the typical hallmarks of cancer, one can mention the switch to aerobic glycolysis as the most favorable mechanism for glucose metabolism and glycome alterations. This review outlines the interconnections between the expression and activity of potassium channels, carbohydrate metabolism, and altered glycosylation in cancer cells, which have not been broadly discussed in the literature hitherto. Moreover, we propose the potential mediators for the described relations (e.g., enzymes, microRNAs) and the novel promising directions (e.g., glycans-orinented drugs) for further research.
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Affiliation(s)
- Agata Wawrzkiewicz-Jałowiecka
- Department of Physical Chemistry and Technology of Polymers, Silesian University of Technology, 44-100 Gliwice, Poland
| | - Anna Lalik
- Department of Systems Biology and Engineering, Silesian University of Technology, 44-100 Gliwice, Poland
- Biotechnology Center, Silesian University of Technology, 44-100 Gliwice, Poland
| | - Agnieszka Lukasiak
- Department of Physics and Biophysics, Institute of Biology, Warsaw University of Life Sciences, 02-776 Warsaw, Poland
| | - Monika Richter-Laskowska
- The Centre for Biomedical Engineering, Łukasiewicz Research Network-Krakow Institute of Technology, 30-418 Krakow, Poland
| | - Paulina Trybek
- Institute of Physics, University of Silesia in Katowice, 41-500 Chorzów, Poland
| | - Maciej Ejfler
- Faculty of Automatic Control, Electronics and Computer Science, Silesian University of Technology, 44-100 Gliwice, Poland
| | - Maciej Opałka
- Faculty of Automatic Control, Electronics and Computer Science, Silesian University of Technology, 44-100 Gliwice, Poland
| | - Sonia Wardejn
- Faculty of Automatic Control, Electronics and Computer Science, Silesian University of Technology, 44-100 Gliwice, Poland
| | - Domenico V Delfino
- Section of Pharmacology, Department of Medicine and Surgery, University of Perugia, 06129 Perugia, Italy
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Brockmueller A, Girisa S, Kunnumakkara AB, Shakibaei M. Resveratrol Modulates Chemosensitisation to 5-FU via β1-Integrin/HIF-1α Axis in CRC Tumor Microenvironment. Int J Mol Sci 2023; 24:ijms24054988. [PMID: 36902421 PMCID: PMC10003050 DOI: 10.3390/ijms24054988] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 02/26/2023] [Accepted: 03/02/2023] [Indexed: 03/08/2023] Open
Abstract
Frequent development of resistance to chemotherapeutic agents such as 5-flourouracil (5-FU) complicates the treatment of advanced colorectal cancer (CRC). Resveratrol is able to utilize β1-integrin receptors, strongly expressed in CRC cells, to transmit and exert anti-carcinogenic signals, but whether it can also utilize these receptors to overcome 5-FU chemoresistance in CRC cells has not yet been investigated. Effects of β1-integrin knockdown on anti-cancer capabilities of resveratrol and 5-FU were investigated in HCT-116 and 5-FU-resistant HCT-116R CRC tumor microenvironment (TME) with 3D-alginate as well as monolayer cultures. Resveratrol increased CRC cell sensitivity to 5-FU by reducing TME-promoted vitality, proliferation, colony formation, invasion tendency and mesenchymal phenotype including pro-migration pseudopodia. Furthermore, resveratrol impaired CRC cells in favor of more effective utilization of 5-FU by down-regulating TME-induced inflammation (NF-kB), vascularisation (VEGF, HIF-1α) and cancer stem cell production (CD44, CD133, ALDH1), while up-regulating apoptosis (caspase-3) that was previously inhibited by TME. These anti-cancer mechanisms of resveratrol were largely abolished by antisense oligonucleotides against β1-integrin (β1-ASO) in both CRC cell lines, indicating the particular importance of β1-integrin receptors for the 5-FU-chemosensitising effect of resveratrol. Lastly, co-immunoprecipitation tests showed that resveratrol targets and modulates the TME-associated β1-integrin/HIF-1α signaling axis in CRC cells. Our results suggest for the first time the utility of the β1-integrin/HIF-1α signaling axis related to chemosensitization and overcoming chemoresistance to 5-FU in CRC cells by resveratrol, underlining its potential supportive applications in CRC treatment.
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Affiliation(s)
- Aranka Brockmueller
- Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilians-University Munich, Pettenkoferstr. 11, D-80336 Munich, Germany
| | - Sosmitha Girisa
- Cancer Biology Laboratory and DBT-AIST International Centre for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati 781039, India
| | - Ajaikumar B. Kunnumakkara
- Cancer Biology Laboratory and DBT-AIST International Centre for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati 781039, India
| | - Mehdi Shakibaei
- Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilians-University Munich, Pettenkoferstr. 11, D-80336 Munich, Germany
- Correspondence: ; Tel.: +49-89-2180-72624
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Zhang Y, Dong X, Guo X, Li C, Fan Y, Liu P, Yuan D, Ma X, Wang J, Zheng J, Li H, Gao P. LncRNA-BC069792 suppresses tumor progression by targeting KCNQ4 in breast cancer. Mol Cancer 2023; 22:41. [PMID: 36859185 PMCID: PMC9976483 DOI: 10.1186/s12943-023-01747-5] [Citation(s) in RCA: 43] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 02/13/2023] [Indexed: 03/03/2023] Open
Abstract
BACKGROUND Breast cancer is the most common malignant tumor that threatens women's health. Attention has been paid on the study of long- non-coding RNA (lncRNA) in breast cancer. However, the specific mechanism remains not clear. METHODS In this study, we explored the role of lncRNA BC069792 in breast cancer. In vitro and in vivo functional experiments were carried out in cell culture and mouse models. High-throughput next-generation sequencing technology and real-time fluorescence quantitative PCR technology were used to evaluate differentially expressed genes and mRNA expression, Western blot and immunohistochemical staining were used to detect protein expression. RNA immunoprecipitation assay and dual-luciferase activity assay were used to evaluate the competing endogenous RNAs (ceRNA), and rescue and mutation experiments were used for verification. RESULTS We found that lncRNA BC069792 was expressed at a low level in breast cancer tissues, and significantly decreased in breast cancer with high pathological grade, lymph node metastasis and high Ki-67 index groups. Moreover, BC069792 inhibited the proliferation, invasion and metastasis of breast cancer cells in vitro and in vivo. Mechanically, BC069792 acts as a molecular sponge to adsorb hsa-miR-658 and hsa-miR-4739, to up-regulate the protein expression of Potassium Voltage-Gated Channel Q4 (KCNQ4), inhibits the activities of JAK2 and p-AKT, and plays a role in inhibiting breast cancer growth. CONCLUSIONS LncRNA BC069792 plays the role of tumor suppressor gene in breast cancer and is a new diagnostic index and therapeutic target in breast cancer.
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Affiliation(s)
- Yunxiang Zhang
- Department of Pathology, The First Clinical Medical College of Weifang Medical University, Weifang people's Hospital, Weifang, 261100, China
| | - Xiaotong Dong
- Department of Pathology, The First Clinical Medical College of Weifang Medical University, Weifang people's Hospital, Weifang, 261100, China
| | - Xiangyu Guo
- Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, 250000, China.,Department of Pathology, Qilu Hospital, Shandong University, Jinan, 250012, China
| | - Chunsen Li
- Department of Pathology, The First Clinical Medical College of Weifang Medical University, Weifang people's Hospital, Weifang, 261100, China
| | - Yanping Fan
- Department of Pathology, The First Clinical Medical College of Weifang Medical University, Weifang people's Hospital, Weifang, 261100, China.,College of Pharmacy, Qingdao University, Qingdao, 266071, China
| | - Pengju Liu
- Department of Economics, Qingdao University, Qingdao, 266061, China
| | - Dawei Yuan
- Qingdao Geneis Institute of Big Data Mining and Precision Medicine, Qingdao, 266000, China
| | - Xialin Ma
- Department of Pathology, The First Clinical Medical College of Weifang Medical University, Weifang people's Hospital, Weifang, 261100, China
| | - Jingru Wang
- Department of Pathology, The First Clinical Medical College of Weifang Medical University, Weifang people's Hospital, Weifang, 261100, China
| | - Jie Zheng
- Department of Diagnostic Pathology, School of Basic Medical Sciences, Weifang Medical University, Weifang, 261053, China
| | - Hongli Li
- Department of Diagnostic Pathology, School of Basic Medical Sciences, Weifang Medical University, Weifang, 261053, China
| | - Peng Gao
- Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, 250000, China. .,Department of Pathology, Qilu Hospital, Shandong University, Jinan, 250012, China.
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Forzisi E, Sesti F. Non-conducting functions of ion channels: The case of integrin-ion channel complexes. Channels (Austin) 2022; 16:185-197. [PMID: 35942524 PMCID: PMC9364710 DOI: 10.1080/19336950.2022.2108565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Started as an academic curiosity more than two decades ago, the idea that ion channels can regulate cellular processes in ways that do not depend on their conducting properties (non-ionic functions) gained traction and is now a flourishing area of research. Channels can regulate physiological processes including actin cytoskeletal remodeling, cell motility, excitation-contraction coupling, non-associative learning and embryogenesis, just to mention some, through non-ionic functions. When defective, non-ionic functions can give rise to channelopathies involved in cancer, neurodegenerative disease and brain trauma. Ion channels exert their non-ionic functions through a variety of mechanisms that range from physical coupling with other proteins, to possessing enzymatic activity, to assembling with signaling molecules. In this article, we take stock of the field and review recent findings. The concept that emerges, is that one of the most common ways through which channels acquire non-ionic attributes, is by assembling with integrins. These integrin-channel complexes exhibit broad genotypic and phenotypic heterogeneity and reveal a pleiotropic nature, as they appear to be capable of influencing both physiological and pathological processes.
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Affiliation(s)
- Elena Forzisi
- Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, Rutgers University, NJ, USA
| | - Federico Sesti
- Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, Rutgers University, NJ, USA
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10
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Boyle Y, Johns TG, Fletcher EV. Potassium Ion Channels in Malignant Central Nervous System Cancers. Cancers (Basel) 2022; 14:cancers14194767. [PMID: 36230692 PMCID: PMC9563970 DOI: 10.3390/cancers14194767] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 09/19/2022] [Accepted: 09/26/2022] [Indexed: 11/16/2022] Open
Abstract
Malignant central nervous system (CNS) cancers are among the most difficult to treat, with low rates of survival and a high likelihood of recurrence. This is primarily due to their location within the CNS, hindering adequate drug delivery and tumour access via surgery. Furthermore, CNS cancer cells are highly plastic, an adaptive property that enables them to bypass targeted treatment strategies and develop drug resistance. Potassium ion channels have long been implicated in the progression of many cancers due to their integral role in several hallmarks of the disease. Here, we will explore this relationship further, with a focus on malignant CNS cancers, including high-grade glioma (HGG). HGG is the most lethal form of primary brain tumour in adults, with the majority of patient mortality attributed to drug-resistant secondary tumours. Hence, targeting proteins that are integral to cellular plasticity could reduce tumour recurrence, improving survival. This review summarises the role of potassium ion channels in malignant CNS cancers, specifically how they contribute to proliferation, invasion, metastasis, angiogenesis, and plasticity. We will also explore how specific modulation of these proteins may provide a novel way to overcome drug resistance and improve patient outcomes.
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Affiliation(s)
- Yasmin Boyle
- Telethon Kids Institute, Perth Children’s Hospital, 15 Hospital Ave, Nedlands, Perth, WA 6009, Australia
- School of Biomedicine, The University of Western Australia, 35 Stirling Hwy, Crawley, Perth, WA 6009, Australia
- Correspondence:
| | - Terrance G. Johns
- Telethon Kids Institute, Perth Children’s Hospital, 15 Hospital Ave, Nedlands, Perth, WA 6009, Australia
- School of Biomedicine, The University of Western Australia, 35 Stirling Hwy, Crawley, Perth, WA 6009, Australia
| | - Emily V. Fletcher
- Telethon Kids Institute, Perth Children’s Hospital, 15 Hospital Ave, Nedlands, Perth, WA 6009, Australia
- School of Biomedicine, The University of Western Australia, 35 Stirling Hwy, Crawley, Perth, WA 6009, Australia
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11
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Katsuda Y, Sato SI, Inoue M, Tsugawa H, Kamura T, Kida T, Matsumoto R, Asamitsu S, Shioda N, Shiroto S, Oosawatsu Y, Yatsuzuka K, Kitamura Y, Hagihara M, Ihara T, Uesugi M. Small molecule-based detection of non-canonical RNA G-quadruplex structures that modulate protein translation. Nucleic Acids Res 2022; 50:8143-8153. [PMID: 35801908 PMCID: PMC9371906 DOI: 10.1093/nar/gkac580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 05/24/2022] [Accepted: 06/23/2022] [Indexed: 11/29/2022] Open
Abstract
Tandem repeats of guanine-rich sequences in RNA often form thermodynamically stable four-stranded RNA structures. Such RNA G-quadruplexes have long been considered to be linked to essential biological processes, yet their physiological significance in cells remains unclear. Here, we report a approach that permits the detection of RNA G-quadruplex structures that modulate protein translation in mammalian cells. The approach combines antibody arrays and RGB-1, a small molecule that selectively stabilizes RNA G-quadruplex structures. Analysis of the protein and mRNA products of 84 cancer-related human genes identified Nectin-4 and CapG as G-quadruplex-controlled genes whose mRNAs harbor non-canonical G-quadruplex structures on their 5′UTR region. Further investigations revealed that the RNA G-quadruplex of CapG exhibits a structural polymorphism, suggesting a possible mechanism that ensures the translation repression in a KCl concentration range of 25–100 mM. The approach described in the present study sets the stage for further discoveries of RNA G-quadruplexes.
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Affiliation(s)
- Yousuke Katsuda
- Division of Materials Science and Chemistry, Faculty of Advanced Science and Technology, Kumamoto University, 2-39-1 Kurokami, Chuo-ku, Kumamoto 860-8555, Japan
| | - Shin-Ichi Sato
- Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan
| | - Maimi Inoue
- Division of Materials Science and Chemistry, Faculty of Advanced Science and Technology, Kumamoto University, 2-39-1 Kurokami, Chuo-ku, Kumamoto 860-8555, Japan
| | - Hisashi Tsugawa
- Graduate School of Science and Technology, Hirosaki University, 3 Bunkyo-cho, Hirosaki, Aomori 036-8561, Japan
| | - Takuto Kamura
- Division of Materials Science and Chemistry, Faculty of Advanced Science and Technology, Kumamoto University, 2-39-1 Kurokami, Chuo-ku, Kumamoto 860-8555, Japan
| | - Tomoki Kida
- Division of Materials Science and Chemistry, Faculty of Advanced Science and Technology, Kumamoto University, 2-39-1 Kurokami, Chuo-ku, Kumamoto 860-8555, Japan
| | - Rio Matsumoto
- Division of Materials Science and Chemistry, Faculty of Advanced Science and Technology, Kumamoto University, 2-39-1 Kurokami, Chuo-ku, Kumamoto 860-8555, Japan
| | - Sefan Asamitsu
- Department of Genomic Neurology, Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan
| | - Norifumi Shioda
- Department of Genomic Neurology, Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan.,Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe, Chuo-ku, Kumamoto 862-0973, Japan
| | - Shuhei Shiroto
- Graduate School of Science and Technology, Hirosaki University, 3 Bunkyo-cho, Hirosaki, Aomori 036-8561, Japan
| | - Yoshiki Oosawatsu
- Division of Materials Science and Chemistry, Faculty of Advanced Science and Technology, Kumamoto University, 2-39-1 Kurokami, Chuo-ku, Kumamoto 860-8555, Japan
| | - Kenji Yatsuzuka
- Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan
| | - Yusuke Kitamura
- Division of Materials Science and Chemistry, Faculty of Advanced Science and Technology, Kumamoto University, 2-39-1 Kurokami, Chuo-ku, Kumamoto 860-8555, Japan
| | - Masaki Hagihara
- Graduate School of Science and Technology, Hirosaki University, 3 Bunkyo-cho, Hirosaki, Aomori 036-8561, Japan
| | - Toshihiro Ihara
- Division of Materials Science and Chemistry, Faculty of Advanced Science and Technology, Kumamoto University, 2-39-1 Kurokami, Chuo-ku, Kumamoto 860-8555, Japan
| | - Motonari Uesugi
- Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan.,School of Pharmacy, Fudan University, Shanghai 201203, China
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12
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Becchetti A, Duranti C, Arcangeli A. Dynamics and physiological meaning of complexes between ion channels and integrin receptors: the case of Kv11.1. Am J Physiol Cell Physiol 2022; 322:C1138-C1150. [PMID: 35442831 DOI: 10.1152/ajpcell.00107.2022] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
The cellular functions are regulated by a complex interplay of diffuse and local signals. Experimental work in cell physiology has led to recognize that understanding a cell's dynamics requires a deep comprehension of local fluctuations of cytosolic regulators. Macromolecular complexes are major determinants of local signaling. Multi-enzyme assemblies limit the diffusion restriction to reaction kinetics by direct exchange of metabolites. Likewise, close coupling of ion channels and transporters modulate the ion concentration around a channel mouth or transporter binding site. Extreme signal locality is brought about by conformational coupling between membrane proteins, as is typical of mechanotransduction. A paradigmatic case is integrin-mediated cell adhesion. Sensing the extracellular microenvironment and providing an appropriate response is essential in growth and development and has innumerable pathological implications. The process involves bidirectional signal transduction by complex supra-molecular structures that link integrin receptors to ion channels and transporters, growth factor receptors, cytoskeletal elements and other regulatory elements. The dynamics of such complexes is only beginning to be understood. A thoroughly studied example is the association between integrin receptors and the voltage-gated K+ channels Kv11.1. These channels are widely expressed in early embryos, where their physiological roles are poorly understood and apparently different from the shaping of action potential firing in the adult. Hints about these roles come from studies in cancer cells, where Kv11.1 is often overexpressed and appears to re-assume functions, such as controlling cell proliferation/differentiation, apoptosis and migration. Kv11.1 is implicated in these processes through its linking to integrin subunits.
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Affiliation(s)
- Andrea Becchetti
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milano, Italy
| | - Claudia Duranti
- Department of Experimental and Clinical Medicine. University of Florence, Firenze, Italy
| | - Annarosa Arcangeli
- Department of Experimental and Clinical Medicine. University of Florence, Firenze, Italy
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13
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Fnu G, Weber GF. Alterations of Ion Homeostasis in Cancer Metastasis: Implications for Treatment. Front Oncol 2022; 11:765329. [PMID: 34988012 PMCID: PMC8721045 DOI: 10.3389/fonc.2021.765329] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 11/23/2021] [Indexed: 12/20/2022] Open
Abstract
We have previously reported that metastases from all malignancies are characterized by a core program of gene expression that suppresses extracellular matrix interactions, induces vascularization/tissue remodeling, activates the oxidative metabolism, and alters ion homeostasis. Among these features, the least elucidated component is ion homeostasis. Here we review the literature with the goal to infer a better mechanistic understanding of the progression-associated ionic alterations and identify the most promising drugs for treatment. Cancer metastasis is accompanied by skewing in calcium, zinc, copper, potassium, sodium and chloride homeostasis. Membrane potential changes and water uptake through Aquaporins may also play roles. Drug candidates to reverse these alterations are at various stages of testing, with some having entered clinical trials. Challenges to their utilization comprise differences among tumor types and the involvement of multiple ions in each case. Further, adverse effects may become a concern, as channel blockers, chelators, or supplemented ions will affect healthy and transformed cells alike.
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Affiliation(s)
- Gulimirerouzi Fnu
- College of Pharmacy, University of Cincinnati Academic Health Center, Cincinnati, OH, United States
| | - Georg F Weber
- College of Pharmacy, University of Cincinnati Academic Health Center, Cincinnati, OH, United States
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14
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Molecular Activation of the Kv11.1 Channel Reprograms EMT in Colon Cancer by Inhibiting TGFβ Signaling via Activation of Calcineurin. Cancers (Basel) 2021; 13:cancers13236025. [PMID: 34885136 PMCID: PMC8656647 DOI: 10.3390/cancers13236025] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Revised: 11/22/2021] [Accepted: 11/24/2021] [Indexed: 12/25/2022] Open
Abstract
Control of ionic gradients is critical to maintain cellular homeostasis in both physiological and pathological conditions, but the role of ion channels in cancer cells has not been studied thoroughly. In this work we demonstrated that activity of the Kv11.1 potassium channel plays a vital role in controlling the migration of colon cancer cells by reversing the epithelial-to-mesenchymal transition (EMT) into the mesenchymal-to-epithelial transition (MET). We discovered that pharmacological stimulation of the Kv11.1 channel with the activator molecule NS1643 produces a strong inhibition of colon cancer cell motility. In agreement with the reversal of EMT, NS1643 treatment leads to a depletion of mesenchymal markers such as SNAIL1, SLUG, TWIST, ZEB, N-cadherin, and c-Myc, while the epithelial marker E-cadherin was strongly upregulated. Investigating the mechanism linking Kv11.1 activity to reversal of EMT into MET revealed that stimulation of Kv11.1 produced a strong and fast inhibition of the TGFβ signaling. Application of NS1643 resulted in de-phosphorylation of the TGFβ downstream effectors R-SMADs by activation of the serine/threonine phosphatase PP2B (calcineurin). Consistent with the role of TGFβ in controlling cancer stemness, NS1643 also produced a strong inhibition of NANOG, SOX2, and OCT4 while arresting the cell cycle in G0/G1. Our data demonstrate that activation of the Kv11.1 channel reprograms EMT into MET by inhibiting TGFβ signaling, which results in inhibition of motility in colon cancer cells.
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15
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Rodat-Despoix L, Chamlali M, Ouadid-Ahidouch H. Ion channels as key partners of cytoskeleton in cancer disease. Biochim Biophys Acta Rev Cancer 2021; 1876:188627. [PMID: 34520803 DOI: 10.1016/j.bbcan.2021.188627] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 09/08/2021] [Accepted: 09/08/2021] [Indexed: 12/14/2022]
Abstract
Several processes occur during tumor development including changes in cell morphology, a reorganization of the expression and distribution of the cytoskeleton proteins as well as ion channels. If cytoskeleton proteins and ion channels have been widely investigated in understanding cancer mechanisms, the interaction between these two elements and the identification of the associated signaling pathways are only beginning to emerge. In this review, we summarize the work published over the past 15 years relating to the roles played by ion channels in these mechanisms of reorganization of the cellular morphology, essential to metastatic dissemination, both through the physical interactions with elements of the cytoskeleton and by intracellular signaling pathways involved.
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Affiliation(s)
- Lise Rodat-Despoix
- Laboratoire de Physiologie Cellulaire et Moléculaire (UR 4667), Université de Picardie Jules Verne, UFR des Sciences, 33 Rue St Leu, 80039 Amiens, France.
| | - Mohamed Chamlali
- Laboratoire de Physiologie Cellulaire et Moléculaire (UR 4667), Université de Picardie Jules Verne, UFR des Sciences, 33 Rue St Leu, 80039 Amiens, France
| | - Halima Ouadid-Ahidouch
- Laboratoire de Physiologie Cellulaire et Moléculaire (UR 4667), Université de Picardie Jules Verne, UFR des Sciences, 33 Rue St Leu, 80039 Amiens, France
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16
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Lou J, Yang X, Shan W, Jin Z, Ding J, Hu Y, Liao Q, Du Q, Xie R, Xu J. Effects of calcium‑permeable ion channels on various digestive diseases in the regulation of autophagy (Review). Mol Med Rep 2021; 24:680. [PMID: 34318907 DOI: 10.3892/mmr.2021.12319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 05/07/2021] [Indexed: 12/09/2022] Open
Abstract
Autophagy is a process of degradation and catabolism in cells. By removing damaged or dysfunctional organelles, autophagy interacts with the ubiquitin‑proteasome degradation system to jointly regulate cell function and energy homeostasis. Since autophagy plays a key role in physiology, disorders of the autophagy mechanism are associated with various diseases. Therefore, thorough understanding of the autophagy regulatory mechanism are crucially important in the diagnosis and treatment of diseases. To date, ion channels may affect the development and treatment of diseases by regulating autophagy, especially calcium‑permeable ion channels, in the process of digestive system diseases. However, the mechanism by which calcium ions and their channels regulate autophagy is still poorly understood, thus emphasizing the need for further research in this field. The present review intends to discuss the association, mechanism and application of calcium ions, their channels and autophagy in the occurrence and development of digestive system diseases.
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Affiliation(s)
- Jun Lou
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Xiaoxu Yang
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Weixi Shan
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Zhe Jin
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Jianhong Ding
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Yanxia Hu
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Qiushi Liao
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Qian Du
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Rui Xie
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Jingyu Xu
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
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17
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Abid MN, Qadir FA, Salihi A. Association between the serum concentrations and mutational status of IL-8, IL-27 and VEGF and the expression levels of the hERG potassium channel gene in patients with colorectal cancer. Oncol Lett 2021; 22:665. [PMID: 34386087 PMCID: PMC8299013 DOI: 10.3892/ol.2021.12926] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 05/21/2021] [Indexed: 11/06/2022] Open
Abstract
The present study aimed to determine the diagnostic value of the serum levels and mutational status of IL-8, IL-27 and VEGF, and the expression levels of human ether-a-go-go-related gene (hERG) in patients with colorectal cancer (CRC). The serum concentrations were determined using the ELISA technique and genotype variations of IL-8, IL-27 and VEGF were examined using Sanger sequencing, and the expression levels of hERG, which encodes a potassium channel, were determined by quantitative PCR, in blood and tissue samples obtained from 80 patients with CRC and 80 healthy individuals. The results of the present study revealed that the percentage of granulocytes and serum concentrations of carcinoembryonic antigen, IL-8 and IL-27 were significantly increased, whereas the percentage of lymphocytes was decreased in patients with CRC. In total, 31 mutations in three genes (eight mutations in VEGF, 13 mutations in IL-27 and 10 mutations in IL-8) were identified in patients with CRC. The relative mRNA expression levels of hERG were also significantly upregulated in tissue and blood samples of patients with CRC compared with those of healthy individuals. In conclusion, the results of the present study indicated that the increased concentrations and genetic variations of IL-8, IL-27 and VEGF may serve important roles in the development and angiogenic processes of CRC. These changes were concomitant with the upregulation of the expression levels of the potassium channel hERG.
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Affiliation(s)
- Marewan N Abid
- Department of Biology, College of Science, Salahaddin University-Erbil, Erbil, Kurdistan Region 44001, Iraq
| | - Fikry A Qadir
- Department of Biology, College of Science, Salahaddin University-Erbil, Erbil, Kurdistan Region 44001, Iraq
| | - Abbas Salihi
- Department of Biology, College of Science, Salahaddin University-Erbil, Erbil, Kurdistan Region 44001, Iraq
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18
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Langthaler S, Rienmüller T, Scheruebel S, Pelzmann B, Shrestha N, Zorn-Pauly K, Schreibmayer W, Koff A, Baumgartner C. A549 in-silico 1.0: A first computational model to simulate cell cycle dependent ion current modulation in the human lung adenocarcinoma. PLoS Comput Biol 2021; 17:e1009091. [PMID: 34157016 PMCID: PMC8219159 DOI: 10.1371/journal.pcbi.1009091] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 05/18/2021] [Indexed: 11/18/2022] Open
Abstract
Lung cancer is still a leading cause of death worldwide. In recent years, knowledge has been obtained of the mechanisms modulating ion channel kinetics and thus of cell bioelectric properties, which is promising for oncological biomarkers and targets. The complex interplay of channel expression and its consequences on malignant processes, however, is still insufficiently understood. We here introduce the first approach of an in-silico whole-cell ion current model of a cancer cell, in particular of the A549 human lung adenocarcinoma, including the main functionally expressed ion channels in the plasma membrane as so far known. This hidden Markov-based model represents the electrophysiology behind proliferation of the A549 cell, describing its rhythmic oscillation of the membrane potential able to trigger the transition between cell cycle phases, and it predicts membrane potential changes over the cell cycle provoked by targeted ion channel modulation. This first A549 in-silico cell model opens up a deeper insight and understanding of possible ion channel interactions in tumor development and progression, and is a valuable tool for simulating altered ion channel function in lung cancer electrophysiology.
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Affiliation(s)
- Sonja Langthaler
- Institute of Health Care Engineering with European Testing Center for Medical Devices, Graz University of Technology, Graz, Austria
| | - Theresa Rienmüller
- Institute of Health Care Engineering with European Testing Center for Medical Devices, Graz University of Technology, Graz, Austria
| | - Susanne Scheruebel
- Research Unit on Ion Channels and Cancer Biology, Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Medical University of Graz, Graz, Austria
| | - Brigitte Pelzmann
- Research Unit on Ion Channels and Cancer Biology, Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Medical University of Graz, Graz, Austria
| | - Niroj Shrestha
- Research Unit on Ion Channels and Cancer Biology, Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Medical University of Graz, Graz, Austria
| | - Klaus Zorn-Pauly
- Research Unit on Ion Channels and Cancer Biology, Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Medical University of Graz, Graz, Austria
| | - Wolfgang Schreibmayer
- Research Unit on Ion Channels and Cancer Biology, Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Medical University of Graz, Graz, Austria
| | - Andrew Koff
- Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York City, New York, United States of America
| | - Christian Baumgartner
- Institute of Health Care Engineering with European Testing Center for Medical Devices, Graz University of Technology, Graz, Austria
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19
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Duranti C, Iorio J, Lottini T, Lastraioli E, Crescioli S, Bagni G, Lulli M, Capitani C, Bouazzi R, Stefanini M, Carraresi L, Iamele L, De Jonge H, Arcangeli A. Harnessing the hERG1/β1 Integrin Complex via a Novel Bispecific Single-chain Antibody: An Effective Strategy against Solid Cancers. Mol Cancer Ther 2021; 20:1338-1349. [PMID: 34045227 DOI: 10.1158/1535-7163.mct-20-1111] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 02/12/2021] [Accepted: 05/14/2021] [Indexed: 11/16/2022]
Abstract
mAbs, either mono- or bispecific (bsAb), represent one of the most successful approaches to treat many types of malignancies. However, there are certain limitations to the use of full length mAbs for clinical applications, which can be overcome by engineered antibody fragments. The aim of this study was to develop a small bsAb, in the format of a single-chain diabody (scDb), to efficiently target two proteins, the hERG1 potassium channel and the β1 subunit of integrin receptors, which specifically form a macromolecular complex in cancer cells. We provide evidence that the scDb we produced binds to the hERG1/β1 complex in cancer cells and tissues, but does not bind to the hERG1 channel in nonpathologic tissues, in particular the heart. The scDb-hERG1-β1 (i) downregulates the formation of the hERG1/β1 complex, (ii) inhibits Akt phosphorylation and HIF-1α expression, and (iii) decreases cell survival, proliferation, and migration in vitro These effects only occur in cancer cells (either colon, pancreatic, or breast), but not in normal cells. In vivo, the scDb-hERG1-β1 shows a good pharmacokinetic profile, with a half-life of 13.5 hours and no general, cardiac, or renal toxicity when injected intravenously up to the dose of 8 mg/kg. The scDb-hERG1-β1 accumulates into subcutaneous xenografted tumors, arising from either colon or pancreatic human cancer cells, and induces a reduction of tumor growth and vascularization. Overall, the scDb-hERG1-β1 represents an innovative single-chain bispecific antibody for therapeutic applications in solid cancers that overexpress the hERG1/β1 integrin signaling complex.
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Affiliation(s)
- Claudia Duranti
- Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence, Firenze, Italy
| | - Jessica Iorio
- Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence, Firenze, Italy
| | - Tiziano Lottini
- Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence, Firenze, Italy
| | - Elena Lastraioli
- Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence, Firenze, Italy
| | - Silvia Crescioli
- Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence, Firenze, Italy
| | - Giacomo Bagni
- Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence, Firenze, Italy
| | - Matteo Lulli
- Department of Biomedical and Clinical Sciences, Section of General Pathology, University of Florence, Firenze, Italy
| | - Chiara Capitani
- Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence, Firenze, Italy
| | - Rayhana Bouazzi
- Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence, Firenze, Italy
| | | | | | - Luisa Iamele
- Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | - Hugo De Jonge
- Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | - Annarosa Arcangeli
- Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence, Firenze, Italy. .,CSDC-Center for the Study of Complex Dynamics, Sesto Fiorentino, Florence, Italy
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20
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Atkinson SP. A preview of selected articles. Stem Cells 2021. [DOI: 10.1002/stem.3364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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21
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Wang D, Liu C, Liu H, Meng Y, Lin F, Gu Y, Wang H, Shang M, Tong C, Sachinidis A, Ying Q, Li L, Peng L. ERG1 plays an essential role in rat cardiomyocyte fate decision by mediating AKT signaling. Stem Cells 2021; 39:443-457. [PMID: 33426760 DOI: 10.1002/stem.3328] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2020] [Accepted: 12/07/2020] [Indexed: 12/13/2022]
Abstract
ERG1, a potassium ion channel, is essential for cardiac action potential repolarization phase. However, the role of ERG1 for normal development of the heart is poorly understood. Using the rat embryonic stem cells (rESCs) model, we show that ERG1 is crucial in cardiomyocyte lineage commitment via interactions with Integrin β1. In the mesoderm phase of rESCs, the interaction of ERG1 with Integrin β1 can activate the AKT pathway by recruiting and phosphorylating PI3K p85 and focal adhesion kinase (FAK) to further phosphorylate AKT. Activation of AKT pathway promotes cardiomyocyte differentiation through two different mechanisms, (a) through phosphorylation of GSK3β to upregulate the expression levels of β-catenin and Gata4; (b) through promotion of nuclear translocation of nuclear factor-κB by phosphorylating IKKβ to inhibit cell apoptosis, which occurs due to increased Bcl2 expression. Our study provides solid evidence for a novel role of ERG1 on differentiation of rESCs into cardiomyocytes.
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Affiliation(s)
- Duo Wang
- Key Laboratory of Arrhythmias, Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.,Heart Health Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.,Institute of Medical Genetics, Tongji University, Shanghai, People's Republic of China
| | - Chang Liu
- Key Laboratory of Arrhythmias, Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.,Heart Health Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.,Institute of Medical Genetics, Tongji University, Shanghai, People's Republic of China
| | - Huan Liu
- Key Laboratory of Arrhythmias, Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.,Heart Health Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.,Institute of Medical Genetics, Tongji University, Shanghai, People's Republic of China
| | - Yilei Meng
- Key Laboratory of Arrhythmias, Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.,Heart Health Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.,Institute of Medical Genetics, Tongji University, Shanghai, People's Republic of China
| | - Fang Lin
- Key Laboratory of Arrhythmias, Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.,Heart Health Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Yanqiong Gu
- Department of Medical Genetics, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Hanrui Wang
- Key Laboratory of Arrhythmias, Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.,Heart Health Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.,Institute of Medical Genetics, Tongji University, Shanghai, People's Republic of China
| | - Mengyue Shang
- Key Laboratory of Arrhythmias, Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.,Heart Health Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.,Institute of Medical Genetics, Tongji University, Shanghai, People's Republic of China
| | - Chang Tong
- Heart Health Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Agapios Sachinidis
- University of Cologne, Institute of Neurophysiology and Center for Molecular Medicine, Cologne (CMMC), Cologne, Germany
| | - Qilong Ying
- Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Li Li
- Key Laboratory of Arrhythmias, Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.,Heart Health Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.,Institute of Medical Genetics, Tongji University, Shanghai, People's Republic of China.,Department of Medical Genetics, Tongji University School of Medicine, Shanghai, People's Republic of China.,Research Units of Origin and Regulation of Heart Rhythm, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| | - Luying Peng
- Key Laboratory of Arrhythmias, Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.,Heart Health Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.,Institute of Medical Genetics, Tongji University, Shanghai, People's Republic of China.,Department of Medical Genetics, Tongji University School of Medicine, Shanghai, People's Republic of China.,Research Units of Origin and Regulation of Heart Rhythm, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
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22
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Pontisso I, Combettes L. Role of Sigma-1 Receptor in Calcium Modulation: Possible Involvement in Cancer. Genes (Basel) 2021; 12:139. [PMID: 33499031 PMCID: PMC7911422 DOI: 10.3390/genes12020139] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 01/15/2021] [Accepted: 01/19/2021] [Indexed: 12/13/2022] Open
Abstract
Ca2+ signaling plays a pivotal role in the control of cellular homeostasis and aberrant regulation of Ca2+ fluxes have a strong impact on cellular functioning. As a consequence of this ubiquitous role, Ca2+ signaling dysregulation is involved in the pathophysiology of multiple diseases including cancer. Indeed, multiple studies have highlighted the role of Ca2+ fluxes in all the steps of cancer progression. In particular, the transfer of Ca2+ at the ER-mitochondrial contact sites, also known as mitochondrial associated membranes (MAMs), has been shown to be crucial for cancer cell survival. One of the proteins enriched at this site is the sigma-1 receptor (S1R), a protein that has been described as a Ca2+-sensitive chaperone that exerts a protective function in cells in various ways, including the modulation of Ca2+ signaling. Interestingly, S1R is overexpressed in many types of cancer even though the exact mechanisms by which it promotes cell survival are not fully elucidated. This review summarizes the findings describing the roles of S1R in the control of Ca2+ signaling and its involvement in cancer progression.
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Affiliation(s)
- Ilaria Pontisso
- UMR 1282, INSERM, Laboratoire de Biologie et Pharmacologie Appliquée, Ecole Normale Supérieure Paris Saclay, 91190 Gif Sur Yvette, France;
- Faculté des Sciences, Université Paris-Saclay, 91405 Orsay, France
| | - Laurent Combettes
- UMR 1282, INSERM, Laboratoire de Biologie et Pharmacologie Appliquée, Ecole Normale Supérieure Paris Saclay, 91190 Gif Sur Yvette, France;
- Faculté des Sciences, Université Paris-Saclay, 91405 Orsay, France
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23
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Influence of Kv11.1 (hERG1) K + channel expression on DNA damage induced by the genotoxic agent methyl methanesulfonate. Pflugers Arch 2021; 473:197-217. [PMID: 33452554 DOI: 10.1007/s00424-021-02517-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 12/22/2020] [Accepted: 01/05/2021] [Indexed: 10/22/2022]
Abstract
Besides their crucial role in cell electrogenesis and maintenance of basal membrane potential, the voltage-dependent K+ channel Kv11.1/hERG1 shows an essential impact in cell proliferation and other processes linked to the maintenance of tumour phenotype. To check the possible influence of channel expression on DNA damage responses, HEK293 cells, treated with the genotoxic agent methyl methanesulfonate (MMS), were compared with those of a HEK-derived cell line (H36), permanently transfected with the Kv11.1-encoding gene, and with a third cell line (T2) obtained under identical conditions as H36, by permanent transfection of another unrelated plasma membrane protein encoding gene. In addition, to gain some insights about the canonical/conduction-dependent channel mechanisms that might be involved, the specific erg channel inhibitor E4031 was used as a tool. Our results indicate that the expression of Kv11.1 does not influence MMS-induced changes in cell cycle progression, because no differences were found between H36 and T2 cells. However, the canonical ion conduction function of the channel appeared to be associated with decreased cell viability at low/medium MMS concentrations. Moreover, direct DNA damage measurements, using the comet assay, demonstrated for the first time that Kv11.1 conduction activity was able to modify MMS-induced DNA damage, decreasing it particularly at high MMS concentration, in a way related to PARP1 gene expression. Finally, our data suggest that the canonical Kv11.1 effects may be relevant for tumour cell responses to anti-tumour therapies.
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24
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Pethő Z, Najder K, Carvalho T, McMorrow R, Todesca LM, Rugi M, Bulk E, Chan A, Löwik CWGM, Reshkin SJ, Schwab A. pH-Channeling in Cancer: How pH-Dependence of Cation Channels Shapes Cancer Pathophysiology. Cancers (Basel) 2020; 12:E2484. [PMID: 32887220 PMCID: PMC7565548 DOI: 10.3390/cancers12092484] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 08/25/2020] [Accepted: 08/26/2020] [Indexed: 12/20/2022] Open
Abstract
Tissue acidosis plays a pivotal role in tumor progression: in particular, interstitial acidosis promotes tumor cell invasion, and is a major contributor to the dysregulation of tumor immunity and tumor stromal cells. The cell membrane and integral membrane proteins commonly act as important sensors and transducers of altered pH. Cell adhesion molecules and cation channels are prominent membrane proteins, the majority of which is regulated by protons. The pathophysiological consequences of proton-sensitive ion channel function in cancer, however, are scarcely considered in the literature. Thus, the main focus of this review is to highlight possible events in tumor progression and tumor immunity where the pH sensitivity of cation channels could be of great importance.
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Affiliation(s)
- Zoltán Pethő
- Institute of Physiology II, University Münster, 48147 Münster, Germany; (K.N.); (L.M.T.); (M.R.); (E.B.); (A.S.)
| | - Karolina Najder
- Institute of Physiology II, University Münster, 48147 Münster, Germany; (K.N.); (L.M.T.); (M.R.); (E.B.); (A.S.)
| | - Tiago Carvalho
- Department of Biosciences, Biotechnologies, and Biopharmaceutics, University of Bari, 90126 Bari, Italy; (T.C.); (S.J.R.)
| | - Roisin McMorrow
- Department of Radiology and Nuclear Medicine, Erasmus Medical Center, 3035 GD Rotterdam, The Netherlands; (R.M.); (C.W.G.M.L.)
| | - Luca Matteo Todesca
- Institute of Physiology II, University Münster, 48147 Münster, Germany; (K.N.); (L.M.T.); (M.R.); (E.B.); (A.S.)
| | - Micol Rugi
- Institute of Physiology II, University Münster, 48147 Münster, Germany; (K.N.); (L.M.T.); (M.R.); (E.B.); (A.S.)
| | - Etmar Bulk
- Institute of Physiology II, University Münster, 48147 Münster, Germany; (K.N.); (L.M.T.); (M.R.); (E.B.); (A.S.)
| | - Alan Chan
- Percuros B.V., 2333 CL Leiden, The Netherlands;
| | - Clemens W. G. M. Löwik
- Department of Radiology and Nuclear Medicine, Erasmus Medical Center, 3035 GD Rotterdam, The Netherlands; (R.M.); (C.W.G.M.L.)
- Department of Oncology CHUV, UNIL and Ludwig Cancer Center, 1011 Lausanne, Switzerland
| | - Stephan J. Reshkin
- Department of Biosciences, Biotechnologies, and Biopharmaceutics, University of Bari, 90126 Bari, Italy; (T.C.); (S.J.R.)
| | - Albrecht Schwab
- Institute of Physiology II, University Münster, 48147 Münster, Germany; (K.N.); (L.M.T.); (M.R.); (E.B.); (A.S.)
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25
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How Dysregulated Ion Channels and Transporters Take a Hand in Esophageal, Liver, and Colorectal Cancer. Rev Physiol Biochem Pharmacol 2020; 181:129-222. [PMID: 32875386 DOI: 10.1007/112_2020_41] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Over the last two decades, the understanding of how dysregulated ion channels and transporters are involved in carcinogenesis and tumor growth and progression, including invasiveness and metastasis, has been increasing exponentially. The present review specifies virtually all ion channels and transporters whose faulty expression or regulation contributes to esophageal, hepatocellular, and colorectal cancer. The variety reaches from Ca2+, K+, Na+, and Cl- channels over divalent metal transporters, Na+ or Cl- coupled Ca2+, HCO3- and H+ exchangers to monocarboxylate carriers and organic anion and cation transporters. In several cases, the underlying mechanisms by which these ion channels/transporters are interwoven with malignancies have been fully or at least partially unveiled. Ca2+, Akt/NF-κB, and Ca2+- or pH-dependent Wnt/β-catenin signaling emerge as cross points through which ion channels/transporters interfere with gene expression, modulate cell proliferation, trigger epithelial-to-mesenchymal transition, and promote cell motility and metastasis. Also miRs, lncRNAs, and DNA methylation represent potential links between the misexpression of genes encoding for ion channels/transporters, their malfunctioning, and cancer. The knowledge of all these molecular interactions has provided the basis for therapeutic strategies and approaches, some of which will be broached in this review.
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26
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Capatina AL, Lagos D, Brackenbury WJ. Targeting Ion Channels for Cancer Treatment: Current Progress and Future Challenges. Rev Physiol Biochem Pharmacol 2020; 183:1-43. [PMID: 32865696 DOI: 10.1007/112_2020_46] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Ion channels are key regulators of cancer cell pathophysiology. They contribute to a variety of processes such as maintenance of cellular osmolarity and membrane potential, motility (via interactions with the cytoskeleton), invasion, signal transduction, transcriptional activity and cell cycle progression, leading to tumour progression and metastasis. Ion channels thus represent promising targets for cancer therapy. Ion channels are attractive targets because many of them are expressed at the plasma membrane and a broad range of existing inhibitors are already in clinical use for other indications. However, many of the ion channels identified in cancer cells are also active in healthy normal cells, so there is a risk that certain blockers may have off-target effects on normal physiological function. This review describes recent research advances into ion channel inhibitors as anticancer therapeutics. A growing body of evidence suggests that a range of existing and novel Na+, K+, Ca2+ and Cl- channel inhibitors may be effective for suppressing cancer cell proliferation, migration and invasion, as well as enhancing apoptosis, leading to suppression of tumour growth and metastasis, either alone or in combination with standard-of-care therapies. The majority of evidence to date is based on preclinical in vitro and in vivo studies, although there are several examples of ion channel-targeting strategies now reaching early phase clinical trials. Given the strong links between ion channel function and regulation of tumour growth, metastasis and chemotherapy resistance, it is likely that further work in this area will facilitate the development of new therapeutic approaches which will reach the clinic in the future.
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Affiliation(s)
| | - Dimitris Lagos
- Hull York Medical School, York, UK
- York Biomedical Research Institute, University of York, York, UK
| | - William J Brackenbury
- Department of Biology, University of York, York, UK.
- York Biomedical Research Institute, University of York, York, UK.
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27
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Iorio J, Duranti C, Lottini T, Lastraioli E, Bagni G, Becchetti A, Arcangeli A. K V11.1 Potassium Channel and the Na +/H + Antiporter NHE1 Modulate Adhesion-Dependent Intracellular pH in Colorectal Cancer Cells. Front Pharmacol 2020; 11:848. [PMID: 32587517 PMCID: PMC7297984 DOI: 10.3389/fphar.2020.00848] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Accepted: 05/22/2020] [Indexed: 12/16/2022] Open
Abstract
Increasing evidence indicates that ion channels and transporters cooperate in regulating different aspects of tumor pathophysiology. In cancer cells, H+/HCO3- transporters usually invert the transmembrane pH gradient typically observed in non-neoplastic cells, which is thought to contribute to cancer malignancy. To what extent the pH-regulating transporters are functionally linked to K+ channels, which are central regulators of cell membrane potential (Vm), is unclear. We thus investigated in colorectal cancer cells the implication of the pH-regulating transporters and KV11.1 (also known as hERG1) in the pH modifications stimulated by integrin-dependent cell adhesion. Colorectal cancer cell lines (HCT 116 and HT 29) were seeded onto β1 integrin-dependent substrates, collagen I and fibronectin. This led to a transient cytoplasmic alkalinization, which peaked at 90 min of incubation, lasted approximately 180 min, and was inhibited by antibodies blocking the β1 integrin. The effect was sensitive to amiloride (10 µM) and cariporide (5 µM), suggesting that it was mainly caused by the activity of the Na+/H+ antiporter NHE1. Blocking KV11.1 with E4031 shows that channel activity contributed to modulate the β1 integrin-dependent pHi increase. Interestingly, both NHE1 and KV11.1 modulated the colorectal cancer cell motility triggered by β1 integrin-dependent adhesion. Finally, the β1 integrin subunit, KV11.1 and NHE1 co-immunoprecipitated in colorectal cancer cells seeded onto Collagen I, suggesting the formation of a macromolecular complex following integrin-mediated adhesion. We conclude that the interaction between KV11.1, NHE1, and β1 integrin contributes to regulate colorectal cancer intracellular pH in relation to the tumor microenvironment, suggesting novel pharmacological targets to counteract pro-invasive and, hence, pro-metastatic behavior in colorectal cancer.
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Affiliation(s)
- Jessica Iorio
- Section of Internal Medicine, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Claudia Duranti
- Section of Internal Medicine, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Tiziano Lottini
- Section of Internal Medicine, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Elena Lastraioli
- Section of Internal Medicine, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Giacomo Bagni
- Section of Internal Medicine, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Andrea Becchetti
- Department of Biotechnology and Biosciences, University of Milano Bicocca, Milano, Italy
| | - Annarosa Arcangeli
- Section of Internal Medicine, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
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28
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Lastraioli E. Focus on Triple-Negative Breast Cancer: Potassium Channel Expression and Clinical Correlates. Front Pharmacol 2020; 11:725. [PMID: 32508650 PMCID: PMC7251142 DOI: 10.3389/fphar.2020.00725] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 05/01/2020] [Indexed: 12/26/2022] Open
Abstract
Despite improvements in early diagnosis and treatment, breast cancer is still a major health problem worldwide. Among breast cancer subtypes, the most challenging and harder to treat is represented by triple-negative molecular subtype. Due to its intrinsic features this subtype cannot be treated neither with hormonal therapy (since it does not express estrogen or progesterone receptors) nor with epidermal growth factor receptor 2 (HER2) inhibitors (as it does not express high levels of this protein). For these reasons, the standard of care for these patients is represented by a combination of surgery, radiation therapy and chemotherapy. In this scenario, searching for novel biomarkers that might help both in diagnosis and therapy is mandatory. In the last years, it was shown that different families of potassium channels are overexpressed in primary breast cancers. The altered ion channel expression may be useful for diagnostic and therapeutic purposes due to some peculiar characteristics of this class of molecules. Ion channels are defined as pore-forming transmembrane proteins regulating passive ion fluxes in the cells. Ion channels represent good potential markers since, being localized at the plasma membrane level, their detection and block with specific drugs and antibodies might be fast and tunable. This review focuses on triple-negative breast cancers and recapitulates the current knowledge about potassium channels' clinical relevance and their potential use in the clinical setting, for triple-negative breast cancer diagnosis and therapy.
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Affiliation(s)
- Elena Lastraioli
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
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29
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Palme D, Misovic M, Ganser K, Klumpp L, Salih HR, Zips D, Huber SM. hERG K + Channels Promote Survival of Irradiated Leukemia Cells. Front Pharmacol 2020; 11:489. [PMID: 32390841 PMCID: PMC7194033 DOI: 10.3389/fphar.2020.00489] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Accepted: 03/27/2020] [Indexed: 12/19/2022] Open
Abstract
Many tumor cells express highly elevated activities of voltage-gated K+ channels in the plasma membrane which are indispensable for tumor growth. To test for K+ channel function during DNA damage response, we subjected human chronic myeloid leukemia (CML) cells to sub-lethal doses of ionizing radiation (0-8 Gy, 6 MV photons) and determined K+ channel activity, K+ channel-dependent Ca2+ signaling, cell cycle progression, DNA repair, and clonogenic survival by whole-cell patch clamp recording, fura-2 Ca2+ imaging, Western blotting, flow cytometry, immunofluorescence microscopy, and pre-plating colony formation assay, respectively. As a result, the human erythroid CML cell line K562 and primary human CML cells functionally expressed hERG1. Irradiation stimulated in both cell types an increase in the activity of hERG1 K+ channels which became apparent 1-2 h post-irradiation. This increase in K+ channel activity was paralleled by an accumulation in S phase of cell cycle followed by a G2/M cell cycle arrest as analyzed between 8 and 72 h post-irradiation. Attenuating the K+ channel function by applying the hERG1 channel inhibitor E4031 modulated Ca2+ signaling, impaired inhibition of the mitosis promoting subunit cdc2, overrode cell cycle arrest, and decreased clonogenic survival of the irradiated cells but did not affect repair of DNA double strand breaks suggesting a critical role of the hERG1 K+ channels for the Ca2+ signaling and the cell cycle control during DNA damage response.
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Affiliation(s)
- Daniela Palme
- Department of Radiation Oncology, University Hospital Tübingen, Tübingen, Germany
| | - Milan Misovic
- Department of Radiation Oncology, University Hospital Tübingen, Tübingen, Germany
| | - Katrin Ganser
- Department of Radiation Oncology, University Hospital Tübingen, Tübingen, Germany
| | - Lukas Klumpp
- Department of Radiation Oncology, University Hospital Tübingen, Tübingen, Germany
| | - Helmut R Salih
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), University Hospital Tübingen, Tübingen, Germany
| | - Daniel Zips
- Department of Radiation Oncology, University Hospital Tübingen, Tübingen, Germany.,German Cancer Consortium (DKTK), Partner Site Tübingen, Tübingen, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Stephan M Huber
- Department of Radiation Oncology, University Hospital Tübingen, Tübingen, Germany
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30
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Tuna M, I Amos C, B Mills G. Acquired Uniparental Disomy Regions Are Associated with Disease Outcome in Patients with Oral Cavity and Oropharynx But Not Larynx Cancers. Transl Oncol 2020; 13:100763. [PMID: 32305020 PMCID: PMC7163079 DOI: 10.1016/j.tranon.2020.100763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 03/11/2020] [Accepted: 03/14/2020] [Indexed: 12/24/2022] Open
Abstract
Acquired uniparental disomy (aUPD) regions pinpoint homozygousity and monoallelic expressed genes. We analyzed The Cancer Genome Atlas single-nucleotide polymorphism arrays and expression data from oral cavity, oropharynx, and larynx cancers to identify frequency of aUPD in each tumor type and association of aUPD regions and differentially expressed genes in the regions with survival. Cox proportional hazard models were used for survival function; and Student’s t test, for differentially expressed genes between groups. The frequency of aUPD was highest in larynx cancers (88.35%) followed by oral cavity (81.11%) and oropharynx cancers (73.85%). In univariate analysis, 11 regions at chromosome 9p were associated with overall survival (OS) in oral cavity cancers. Two regions at chromosome 17p were associated with OS in oropharyngeal cancers, but no aUPD region was associated with survival in patients with larynx cancers. Overexpression of SIGMAR1, C9orf23, and HINT2 was associated with reduced OS in patients with oral cavity cancers, and upregulation of MED27 and YWHAE was associated with shorter OS in patients with oropharynx cancers. In multivariate analysis, four aUPD regions at chromosome 9p and overexpression of HINT2 were associated with shorter OS in oral cavity cancers, and overexpression of MED27 was associated with worse OS in patients with oropharynx cancers. aUPD regions and differentially expressed genes in those regions influence the outcome and may play a role in aggressiveness in oral cavity and oropharynx cancers but not in patients with larynx cancers.
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Affiliation(s)
- Musaffe Tuna
- Department of Medicine, Baylor College of Medicine, Houston, TX.
| | - Christopher I Amos
- Department of Medicine, Baylor College of Medicine, Houston, TX; Institute of Clinical and Translational Research, Baylor College of Medicine, Houston, TX
| | - Gordon B Mills
- Department of Cell, Developmental & Cancer Biology, School of Medicine, Oregon Health Science University, Portland, OR; Precision Oncology, Knight Cancer Institute, Oregon Health Science University, Portland, OR
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31
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Clarithromycin inhibits autophagy in colorectal cancer by regulating the hERG1 potassium channel interaction with PI3K. Cell Death Dis 2020; 11:161. [PMID: 32123164 PMCID: PMC7052256 DOI: 10.1038/s41419-020-2349-8] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 02/07/2020] [Accepted: 02/10/2020] [Indexed: 12/12/2022]
Abstract
We have studied how the macrolide antibiotic Clarithromycin (Cla) regulates autophagy, which sustains cell survival and resistance to chemotherapy in cancer. We found Cla to inhibit the growth of human colorectal cancer (CRC) cells, by modulating the autophagic flux and triggering apoptosis. The accumulation of cytosolic autophagosomes accompanied by the modulation of autophagic markers LC3-II and p62/SQSTM1, points to autophagy exhaustion. Because Cla is known to bind human Ether-à-go-go Related Gene 1 (hERG1) K+ channels, we studied if its effects depended on hERG1 and its conformational states. By availing of hERG1 mutants with different gating properties, we found that fluorescently labelled Cla preferentially bound to the closed channels. Furthermore, by sequestering the channel in the closed conformation, Cla inhibited the formation of a macromolecular complex between hERG1 and the p85 subunit of PI3K. This strongly reduced Akt phosphorylation, and stimulated the p53-dependent cell apoptosis, as witnessed by late caspase activation. Finally, Cla enhanced the cytotoxic effect of 5-fluorouracil (5-FU), the main chemotherapeutic agent in CRC, in vitro and in a xenograft CRC model. We conclude that Cla affects the autophagic flux by impairing the signaling pathway linking hERG1 and PI3K. Combining Cla with 5-FU might be a novel therapeutic option in CRC.
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32
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Iorio J, Lastraioli E, Tofani L, Petroni G, Antonuzzo L, Messerini L, Perrone G, Caputo D, Francesconi M, Amato MM, Cadei M, Arcangeli G, Villanacci V, Boni L, Coppola R, Di Costanzo F, Arcangeli A. hERG1 and HIF-2α Behave as Biomarkers of Positive Response to Bevacizumab in Metastatic Colorectal Cancer Patients. Transl Oncol 2020; 13:100740. [PMID: 32105990 PMCID: PMC7044526 DOI: 10.1016/j.tranon.2020.01.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Accepted: 01/09/2020] [Indexed: 12/22/2022] Open
Abstract
Background: In search of novel biomarkers of response to bevacizumab in metastatic colorectal cancer (mCRC), we analyzed the expression and prognostic role of several proteins related to angiogenesis. Methods: A retrospective, multicenter study on 80 surgical samples from mCRC patients treated in first line with bevacizumab plus chemotherapy was accomplished. The following proteins were analyzed by immunohistochemistry: hERG1 potassium channel, β1-integrin, pAKT, NFkB, HIF-1α, HIF-2α, p53, VEGF-A, GLUT-1, and CA-IX. Data were analyzed in conjunction with the clinicopathological characteristics of the patients, KRAS status, response to bevacizumab, and follow-up. Results: (1) All the proteins were expressed in the samples, with statistically significant associations between HIF-1α and gender, HIF-2α and left colon, hERG1 and VEGF-A, β1-integrin and HIF-2α, GLUT-1 and both HIF-1α and HIF-2α, and CA-IX and VEGF-A. (2) At the univariate analysis, positivity for hERG1, VEGF-A, and the active form of HIF-2α (aHIF-2α), and the G3 histological grade showed a positive impact on progression-free survival (PFS). (3) hERG1 and aHIF-2α maintained their positive impact on PFS at the multivariate analysis. (4) hERG1 behaved as a protective factor for PFS independently on KRAS status. Conclusions: hERG1 and aHIF-2α might help to identify patients who would benefit from bevacizumab treatment.
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Affiliation(s)
- Jessica Iorio
- Department of Experimental and Clinical Medicine, University of Florence, Italy; Department of Medical Biotechnologies, University of Siena, Italy
| | - Elena Lastraioli
- Department of Experimental and Clinical Medicine, University of Florence, Italy
| | - Lorenzo Tofani
- Department of Neurosciences, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy
| | - Giulia Petroni
- Department of Experimental and Clinical Medicine, University of Florence, Italy
| | - Lorenzo Antonuzzo
- Department of Medical Biotechnologies, University of Siena, Italy; Medical Oncology, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy
| | - Luca Messerini
- Department of Experimental and Clinical Medicine, University of Florence, Italy
| | - Giuseppe Perrone
- Department of Pathology, Campus Bio-Medico University of Rome, Italy
| | - Damiano Caputo
- Department of General Surgery, Campus Bio-Medico University of Rome, Italy
| | - Maria Francesconi
- Department of Pathology, Campus Bio-Medico University of Rome, Italy
| | | | - Moris Cadei
- Institute of Pathology, ASST Spedali Civili di Brescia, Brescia, Italy
| | | | | | - Luca Boni
- Department of Neurosciences, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy
| | - Roberto Coppola
- Department of General Surgery, Campus Bio-Medico University of Rome, Italy
| | | | - Annarosa Arcangeli
- Department of Experimental and Clinical Medicine, University of Florence, Italy.
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33
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Girault A, Ahidouch A, Ouadid-Ahidouch H. Roles for Ca 2+ and K + channels in cancer cells exposed to the hypoxic tumour microenvironment. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2020; 1867:118644. [PMID: 31931022 DOI: 10.1016/j.bbamcr.2020.118644] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 12/26/2019] [Accepted: 12/31/2019] [Indexed: 02/07/2023]
Abstract
For twenty years, ion channels have been studied in cancer progression. Several information have been collected about their involvement in cancer cellular processes like cell proliferation, motility and their participation in tumour progression using in-vivo models. Tumour microenvironment is currently the focus of many researches and the highlighting of the relationship between cancer cells and surrounding elements, is expanding. One of the major physic-chemical parameter involved in tumour progression is the hypoxia conditions observed in solid cancer. Due to their position on the cell membrane, ion channels are good candidates to transduce or to be modulated by environmental modifications. Until now, few reports have been interested in the modification of ion channel activities or expression in this context, compared to other pathological situations such as ischemia reperfusion. The aim of our review is to summarize the current knowledge about the calcium and potassium channels properties in the context of hypoxia in tumours. This review could pave the way to orientate new studies around this exciting field to obtain new potential therapeutic approaches.
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Affiliation(s)
- Alban Girault
- Université de Picardie Jules Verne, UFR des Sciences, Laboratoire de Physiologie Cellulaire et Moléculaire (EA 4667), Amiens, France
| | - Ahmed Ahidouch
- Université de Picardie Jules Verne, UFR des Sciences, Laboratoire de Physiologie Cellulaire et Moléculaire (EA 4667), Amiens, France; Université Ibn Zohr, Faculté des sciences, Département de Biologie, Agadir, Morocco
| | - Halima Ouadid-Ahidouch
- Université de Picardie Jules Verne, UFR des Sciences, Laboratoire de Physiologie Cellulaire et Moléculaire (EA 4667), Amiens, France.
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hERG1 and CA IX expression are associated with disease recurrence in surgically resected clear cell renal carcinoma. Eur J Surg Oncol 2019; 46:209-215. [PMID: 31679954 DOI: 10.1016/j.ejso.2019.10.031] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Revised: 10/22/2019] [Accepted: 10/25/2019] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND In search of novel prognostic biomarkers for clear cell renal carcinoma (ccRCC), we analysed the expression of several proteins related to angiogenesis and hypoxia. METHODS A monocentric study on 30 consecutive surgical samples from surgically-treated ccRCC patients with a 10-year follow up was performed. The following proteins were analysed by immunohistochemistry: Vascular Endothelial Growth Factor- A (VEGF-A), Platelet-Derived Growth Factor β Receptor (PDGFRβ), VEGF-receptor 1 (Flt1), VEGF-receptor 2 (KDR), Glucose Transporter 1 (GLUT1), Carbonic anhydrase IX (CA-IX) and the hERG1 potassium channel. Data were analysed in conjunction with the clinico-pathological characteristics of the patients and follow up. RESULTS All the proteins were expressed in the samples, with statistically significant associations of VEGF-A with PDGFRβ and Flt1 and hERG1 with CA IX. Notably, hERG1 and CAIX co-immunoprecipitated in primary ccRCC samples and survival analysis showed that the positivity for hERG1 and CA IX had a negative impact on Recurrence Free Survival (RFS) at the univariate analysis. At the multivariate analysis only hERG1 maintained its statistically significant negative impact. CONCLUSIONS hERG1 expression can be exploited to predict recurrence in surgically-treated ccRCC patients. hERG1 channels form a multiprotein complex with the pH regulator CA IX in primary ccRCC samples their potential use as therapeutic target might be suggested.
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Anderson KJ, Cormier RT, Scott PM. Role of ion channels in gastrointestinal cancer. World J Gastroenterol 2019; 25:5732-5772. [PMID: 31636470 PMCID: PMC6801186 DOI: 10.3748/wjg.v25.i38.5732] [Citation(s) in RCA: 133] [Impact Index Per Article: 22.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2019] [Revised: 07/26/2019] [Accepted: 09/27/2019] [Indexed: 02/06/2023] Open
Abstract
In their seminal papers Hanahan and Weinberg described oncogenic processes a normal cell undergoes to be transformed into a cancer cell. The functions of ion channels in the gastrointestinal (GI) tract influence a variety of cellular processes, many of which overlap with these hallmarks of cancer. In this review we focus on the roles of the calcium (Ca2+), sodium (Na+), potassium (K+), chloride (Cl-) and zinc (Zn2+) transporters in GI cancer, with a special emphasis on the roles of the KCNQ1 K+ channel and CFTR Cl- channel in colorectal cancer (CRC). Ca2+ is a ubiquitous second messenger, serving as a signaling molecule for a variety of cellular processes such as control of the cell cycle, apoptosis, and migration. Various members of the TRP superfamily, including TRPM8, TRPM7, TRPM6 and TRPM2, have been implicated in GI cancers, especially through overexpression in pancreatic adenocarcinomas and down-regulation in colon cancer. Voltage-gated sodium channels (VGSCs) are classically associated with the initiation and conduction of action potentials in electrically excitable cells such as neurons and muscle cells. The VGSC NaV1.5 is abundantly expressed in human colorectal CRC cell lines as well as being highly expressed in primary CRC samples. Studies have demonstrated that conductance through NaV1.5 contributes significantly to CRC cell invasiveness and cancer progression. Zn2+ transporters of the ZIP/SLC39A and ZnT/SLC30A families are dysregulated in all major GI organ cancers, in particular, ZIP4 up-regulation in pancreatic cancer (PC). More than 70 K+ channel genes, clustered in four families, are found expressed in the GI tract, where they regulate a range of cellular processes, including gastrin secretion in the stomach and anion secretion and fluid balance in the intestinal tract. Several distinct types of K+ channels are found dysregulated in the GI tract. Notable are hERG1 upregulation in PC, gastric cancer (GC) and CRC, leading to enhanced cancer angiogenesis and invasion, and KCNQ1 down-regulation in CRC, where KCNQ1 expression is associated with enhanced disease-free survival in stage II, III, and IV disease. Cl- channels are critical for a range of cellular and tissue processes in the GI tract, especially fluid balance in the colon. Most notable is CFTR, whose deficiency leads to mucus blockage, microbial dysbiosis and inflammation in the intestinal tract. CFTR is a tumor suppressor in several GI cancers. Cystic fibrosis patients are at a significant risk for CRC and low levels of CFTR expression are associated with poor overall disease-free survival in sporadic CRC. Two other classes of chloride channels that are dysregulated in GI cancers are the chloride intracellular channels (CLIC1, 3 & 4) and the chloride channel accessory proteins (CLCA1,2,4). CLIC1 & 4 are upregulated in PC, GC, gallbladder cancer, and CRC, while the CLCA proteins have been reported to be down-regulated in CRC. In summary, it is clear, from the diverse influences of ion channels, that their aberrant expression and/or activity can contribute to malignant transformation and tumor progression. Further, because ion channels are often localized to the plasma membrane and subject to multiple layers of regulation, they represent promising clinical targets for therapeutic intervention including the repurposing of current drugs.
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Affiliation(s)
- Kyle J Anderson
- Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812, United States
| | - Robert T Cormier
- Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812, United States
| | - Patricia M Scott
- Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812, United States
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Iorio J, Petroni G, Duranti C, Lastraioli E. Potassium and Sodium Channels and the Warburg Effect: Biophysical Regulation of Cancer Metabolism. Bioelectricity 2019; 1:188-200. [PMID: 34471821 PMCID: PMC8370285 DOI: 10.1089/bioe.2019.0017] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Ion channels are progressively emerging as a novel class of membrane proteins expressed in several types of human cancers and regulating the different aspects of cancer cell behavior. The metabolism of cancer cells, usually composed by a variable proportion of respiration, glycolysis, and glutaminolysis, leads to the excessive production of acidic metabolic products. The presence of these acidic metabolites inside the cells results in intracellular acidosis, and hinders survival and proliferation. For this reason, tumor cells activate mechanisms of pH control that produce a constitutive increase in intracellular pH (pHi) that is more acidic than the extracellular pH (pHe). This condition forms a perfect microenvironment for metastatic progression and may be permissive for some of the acquired characteristics of tumors. Recent analyses have revealed complex interconnections between oncogenic activation, ion channels, hypoxia signaling and metabolic pathways that are dysregulated in cancer. Here, we summarize the molecular mechanisms of the Warburg effect and hypoxia and their association. Moreover, we discuss the recent findings concerning the involvement of ion channels in various aspects of the Warburg effect and hypoxia, focusing on the role of Na+ and K+ channels in hypoxic and metabolic reprogramming in cancer.
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Affiliation(s)
- Jessica Iorio
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Giulia Petroni
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Claudia Duranti
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Elena Lastraioli
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
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Wang H, Yang X, Guo Y, Shui L, Li S, Bai Y, Liu Y, Zeng M, Xia J. HERG1 promotes esophageal squamous cell carcinoma growth and metastasis through TXNDC5 by activating the PI3K/AKT pathway. J Exp Clin Cancer Res 2019; 38:324. [PMID: 31331361 PMCID: PMC6647263 DOI: 10.1186/s13046-019-1284-y] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Accepted: 06/19/2019] [Indexed: 02/05/2023] Open
Abstract
Background The human ether a-go-go-related gene 1 (HERG1) is involved in tumor progression; however, its role in esophageal squamous cell carcinoma (ESCC) is not well studied. This study investigated HERG1 function in ESCC progression and elucidated the underlying mechanisms. Methods The prognostic value of HERG1 was determined by immunohistochemistry in ESCC biopsies. Cell growth and proliferation were analyzed by colony formation and methyl thiazolyl tetrazolium assays. Cell migration and invasion were analyzed by wound healing and Boyden transwell assays. Epithelial-mesenchymal transition (EMT) was evaluated by immunoblotting and quantitative polymerase chain reaction (qPCR). A xenograft mouse model was used to validate the tumorigenic and metastatic roles of HERG1 in vivo. Results HERG1 expression was overall higher in ESCC tissues compared to adjacent non-tumor tissues. A retrospective analysis of 349 patients with ESCC (stages I–IV) confirmed increased HERG1 expression was associated with disease progression and higher mortality rate. The overall survival of the patients was significantly worse when their tumors displayed higher HERG1 expression. HERG1 knockdown reduced tumor growth and metastasis in athymic mice. HERG1 affected the proliferation, migration, and invasion of two ESCC cell lines (TE-1 and KYSE-30). Changes in HERG1 expression affected the expression of cell cycle- and EMT-related proteins; these effects were reversed by altering the expression of thioredoxin domain-containing protein 5 (TXNDC5), which is also associated with the clinicopathological characteristics of patients with ESCC and is relevant to HERG1 in pathological biopsies. Additionally, HERG1 expression altered phosphoinositide 3-kinase (PI3K) and AKT phosphorylation, thereby affecting TXNDC5 expression. Conclusions HERG1 contributes to poor prognosis in patients with ESCC by promoting ESCC cell proliferation, migration, and invasion via TXNDC5 through the PI3K/AKT signaling pathway. Our findings provided novel insights into the pathology of ESCC and role of HERG1 in tumor progression, suggesting that targeting HERG1 has potential diagnostic and therapeutic value for ESCC treatment. Electronic supplementary material The online version of this article (10.1186/s13046-019-1284-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Hongqiang Wang
- Cancer Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.,Department of Oncology, Zhejiang Province Zhoushan Hospital, Zhoushan, China
| | - Xuchun Yang
- Department of Oncology, Zhejiang Province Zhoushan Hospital, Zhoushan, China
| | - Yan Guo
- Cancer Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Lin Shui
- Department of Oncology, West China Hospital, West China Medical Center, Sichuan University, Chengdu, China
| | - Shi Li
- Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yifeng Bai
- Cancer Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Yu Liu
- Cancer Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Ming Zeng
- Cancer Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Jianling Xia
- Cancer Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.
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Marzo T, Massai L, Pratesi A, Stefanini M, Cirri D, Magherini F, Becatti M, Landini I, Nobili S, Mini E, Crociani O, Arcangeli A, Pillozzi S, Gamberi T, Messori L. Replacement of the Thiosugar of Auranofin with Iodide Enhances the Anticancer Potency in a Mouse Model of Ovarian Cancer. ACS Med Chem Lett 2019; 10:656-660. [PMID: 30996813 DOI: 10.1021/acsmedchemlett.9b00007] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Accepted: 02/07/2019] [Indexed: 12/13/2022] Open
Abstract
In recent years, a few successful attempts were made to repurpose the clinically approved antiarthritic gold drug, Auranofin (AF), as an anticancer agent. The present study shows that the iodido(triethylphosphine)gold(I) complex, (Et 3 PAuI hereafter)-an AF analogue where the thiosugar ligand is simply replaced by one iodide ligand-manifests a solution chemistry resembling that of AF and exerts similar cytotoxic and proapoptotic effects on A2780 human ovarian cancer cells in vitro. However, when evaluated in a preclinical orthotopic model of ovarian cancer, Et 3 PAuI produces a far superior anticancer action than AF inducing a nearly complete tumor remission. The highly promising in vivo performances here documented for Et 3 PAuI warrant its further evaluation as a drug candidate for ovarian cancer treatment.
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Affiliation(s)
- Tiziano Marzo
- Department of Pharmacy, University of Pisa, via Bonanno Pisano 6, 56126 Pisa, Italy
| | - Lara Massai
- Laboratory of Metals in Medicine (MetMed), Department of Chemistry “U. Schiff”, University of Florence, via della Lastruccia 3, 50019 Sesto Fiorentino, Italy
| | - Alessandro Pratesi
- Laboratory of Metals in Medicine (MetMed), Department of Chemistry “U. Schiff”, University of Florence, via della Lastruccia 3, 50019 Sesto Fiorentino, Italy
| | - Matteo Stefanini
- DI.V.A.L. Toscana s.r.l., via Madonna del Piano 6, 50019 Sesto Fiorentino, Italy
| | - Damiano Cirri
- Laboratory of Metals in Medicine (MetMed), Department of Chemistry “U. Schiff”, University of Florence, via della Lastruccia 3, 50019 Sesto Fiorentino, Italy
| | - Francesca Magherini
- Department of Biochemical, Experimental and Clinical Sciences “Mario Serio”, University of Florence, viale G.B. Morgagni 50, 50134 Firenze, Italy
| | - Matteo Becatti
- Department of Biochemical, Experimental and Clinical Sciences “Mario Serio”, University of Florence, viale G.B. Morgagni 50, 50134 Firenze, Italy
| | - Ida Landini
- Department of Health Sciences, University of Florence, viale Pieraccini 6, 50139 Firenze, Italy
| | - Stefania Nobili
- Department of Health Sciences, University of Florence, viale Pieraccini 6, 50139 Firenze, Italy
| | - Enrico Mini
- Department of Health Sciences, University of Florence, viale Pieraccini 6, 50139 Firenze, Italy
| | - Olivia Crociani
- DI.V.A.L. Toscana s.r.l., via Madonna del Piano 6, 50019 Sesto Fiorentino, Italy
| | - Annarosa Arcangeli
- Department of Experimental and Clinical Medicine, University of Florence, viale G.B. Morgagni 50, 50134 Firenze, Italy
| | - Serena Pillozzi
- DI.V.A.L. Toscana s.r.l., via Madonna del Piano 6, 50019 Sesto Fiorentino, Italy
- Department of Experimental and Clinical Medicine, University of Florence, viale G.B. Morgagni 50, 50134 Firenze, Italy
| | - Tania Gamberi
- Department of Biochemical, Experimental and Clinical Sciences “Mario Serio”, University of Florence, viale G.B. Morgagni 50, 50134 Firenze, Italy
| | - Luigi Messori
- Laboratory of Metals in Medicine (MetMed), Department of Chemistry “U. Schiff”, University of Florence, via della Lastruccia 3, 50019 Sesto Fiorentino, Italy
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Implication of Voltage-Gated Potassium Channels in Neoplastic Cell Proliferation. Cancers (Basel) 2019; 11:cancers11030287. [PMID: 30823672 PMCID: PMC6468671 DOI: 10.3390/cancers11030287] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2019] [Revised: 02/21/2019] [Accepted: 02/24/2019] [Indexed: 12/12/2022] Open
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 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.
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Becchetti A, Petroni G, Arcangeli A. Ion Channel Conformations Regulate Integrin-Dependent Signaling. Trends Cell Biol 2019; 29:298-307. [PMID: 30635161 DOI: 10.1016/j.tcb.2018.12.005] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 12/16/2018] [Accepted: 12/18/2018] [Indexed: 01/12/2023]
Abstract
Cell-matrix adhesion determines the choice between different cell fates and is accompanied by substantial changes in ion transport. The greatest evidence is the bidirectional interplay occurring between integrin receptors and K+ channels. These proteins can form signaling hubs that regulate cell proliferation, differentiation, and migration in normal and neoplastic tissue. Recent results show that the physical interaction with integrins determines the balance of the open and closed K+ channel states, and individual channel conformations regulate distinct downstream pathways. We propose a model of how these mechanisms regulate proliferation and metastasis in cancer cells. In particular, we suggest that the neoplastic progression could be modulated by targeting specific ion channel conformations.
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Affiliation(s)
- Andrea Becchetti
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milano, Italy.
| | - Giulia Petroni
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Firenze, Italy
| | - Annarosa Arcangeli
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Firenze, Italy
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Prevarskaya N, Skryma R, Shuba Y. Ion Channels in Cancer: Are Cancer Hallmarks Oncochannelopathies? Physiol Rev 2018; 98:559-621. [PMID: 29412049 DOI: 10.1152/physrev.00044.2016] [Citation(s) in RCA: 302] [Impact Index Per Article: 43.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Genomic instability is a primary cause and fundamental feature of human cancer. However, all cancer cell genotypes generally translate into several common pathophysiological features, often referred to as cancer hallmarks. Although nowadays the catalog of cancer hallmarks is quite broad, the most common and obvious of them are 1) uncontrolled proliferation, 2) resistance to programmed cell death (apoptosis), 3) tissue invasion and metastasis, and 4) sustained angiogenesis. Among the genes affected by cancer, those encoding ion channels are present. Membrane proteins responsible for signaling within cell and among cells, for coupling of extracellular events with intracellular responses, and for maintaining intracellular ionic homeostasis ion channels contribute to various extents to pathophysiological features of each cancer hallmark. Moreover, tight association of these hallmarks with ion channel dysfunction gives a good reason to classify them as special type of channelopathies, namely oncochannelopathies. Although the relation of cancer hallmarks to ion channel dysfunction differs from classical definition of channelopathies, as disease states causally linked with inherited mutations of ion channel genes that alter channel's biophysical properties, in a broader context of the disease state, to which pathogenesis ion channels essentially contribute, such classification seems absolutely appropriate. In this review the authors provide arguments to substantiate such point of view.
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Affiliation(s)
- Natalia Prevarskaya
- INSERM U-1003, Equipe Labellisée par la Ligue Nationale contre le Cancer et LABEX, Université Lille1 , Villeneuve d'Ascq , France ; Bogomoletz Institute of Physiology and International Center of Molecular Physiology, NASU, Kyiv-24, Ukraine
| | - Roman Skryma
- INSERM U-1003, Equipe Labellisée par la Ligue Nationale contre le Cancer et LABEX, Université Lille1 , Villeneuve d'Ascq , France ; Bogomoletz Institute of Physiology and International Center of Molecular Physiology, NASU, Kyiv-24, Ukraine
| | - Yaroslav Shuba
- INSERM U-1003, Equipe Labellisée par la Ligue Nationale contre le Cancer et LABEX, Université Lille1 , Villeneuve d'Ascq , France ; Bogomoletz Institute of Physiology and International Center of Molecular Physiology, NASU, Kyiv-24, Ukraine
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Iorio J, Meattini I, Bianchi S, Bernini M, Maragna V, Dominici L, Casella D, Vezzosi V, Orzalesi L, Nori J, Livi L, Arcangeli A, Lastraioli E. hERG1 channel expression associates with molecular subtypes and prognosis in breast cancer. Cancer Cell Int 2018; 18:93. [PMID: 30002601 PMCID: PMC6034270 DOI: 10.1186/s12935-018-0592-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Accepted: 06/26/2018] [Indexed: 12/30/2022] Open
Abstract
Background Breast cancer (BC) is the most frequent malignancy among females worldwide. Despite several efforts and improvements in early diagnosis and treatment, there are still tumors characterized by an aggressive behavior due to unfavorable biology, thus quite difficult to treat. In this view, searching for novel potential biomarkers is mandatory. Among them, in the recent years data have been gathered addressing ion channel as important players in oncology. Methods A retrospective pilot study was performed on 40 BC samples by means of immunohistochemistry in order to evaluate hERG1 potassium channels expression in BC. Results We provide evidence that hERG1 is expressed in all the BC samples analyzed. hERG1 expression was significantly associated with molecular subtype with the highest expression in Luminal A and the lowest in basal-like tumors (p = 0.001), tumor grading (the highest hERG1 expression in well-moderate differentiated tumors, p = 0.020), estrogen receptors (high hERG1 expression in ER-positive samples, p = 0.008) and Ki67 proliferative index (high hERG1 scoring in samples with low proliferative index, p = 0.038). Also, a p value close to significance was noticed for the association between hERG1 and HER2 expression (p = 0.079). At the survival analysis, patients with high hERG1 expression turned out to have a longer progression-free survival, although statistical significance was not reached (p = 0.195). The same trend was observed analyzing local relapse free-survival (LRFS) and metastases-free survival (MFS): patients with higher hERG1 scoring had longer LRFS and MFS (p = 0.124 and p = 0.071, respectively). Conclusions The results of this pilot study provide the first evidence that the hERG1 protein is expressed in primary BC, and its expression associates with molecular subtype. hERG1 apparently behaves as a protective factor, since it contributes to identify a subset of patients with better outcome. Overall, these data suggest that hERG1 might be an additional tool for the management of BC, nevertheless further investigations are warranted to better clarify hERG1 role and clinical usefulness in BC.
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Affiliation(s)
- Jessica Iorio
- 1Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence, Viale GB Morgagni, 50, 50134 Florence, Italy.,2Doctorate Course in Genetics, Oncology and Clinical Medicine, University of Siena, Siena, Italy
| | - Icro Meattini
- Radiation Oncology Unit, Department of Oncology, University of Florence, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy
| | - Simonetta Bianchi
- 4Section of Pathological Anatomy, Department of Surgery and Translational Medicine, University of Florence-Azienda Ospedaliero-Universitaria Careggi, Florence, Italy
| | - Marco Bernini
- 5Breast Unit Surgery, Department of Oncology, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy
| | - Virginia Maragna
- Radiation Oncology Unit, Department of Oncology, University of Florence, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy
| | - Luca Dominici
- Radiation Oncology Unit, Department of Oncology, University of Florence, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy
| | - Donato Casella
- 5Breast Unit Surgery, Department of Oncology, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy
| | - Vania Vezzosi
- 4Section of Pathological Anatomy, Department of Surgery and Translational Medicine, University of Florence-Azienda Ospedaliero-Universitaria Careggi, Florence, Italy
| | - Lorenzo Orzalesi
- 5Breast Unit Surgery, Department of Oncology, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy
| | - Jacopo Nori
- Diagnostic Senology Unit, University of Florence, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy
| | - Lorenzo Livi
- Radiation Oncology Unit, Department of Oncology, University of Florence, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy
| | - Annarosa Arcangeli
- 1Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence, Viale GB Morgagni, 50, 50134 Florence, Italy
| | - Elena Lastraioli
- 1Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence, Viale GB Morgagni, 50, 50134 Florence, Italy
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Ketchem CJ, Kucera C, Barve A, Beverly LJ. The Antiarrhythmic Drug, Amiodarone, Decreases AKT Activity and Sensitizes Human Acute Myeloid Leukemia Cells to Apoptosis by ABT-263. Am J Med Sci 2018; 355:488-496. [PMID: 29753379 DOI: 10.1016/j.amjms.2018.01.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Revised: 01/22/2018] [Accepted: 01/22/2018] [Indexed: 01/12/2023]
Abstract
BACKGROUND Successful treatment of leukemia requires new medications to combat drug resistance, but the development of novel therapies is an arduous and risky endeavor. Repurposing currently approved drugs or those already in clinical development to treat other indications is a more practical approach. Moreover, combinatorial therapeutics are often more efficacious than single agent therapeutics because the former can simultaneously target multiple pathways that mitigate tumor aggressiveness and induce cancer cell death. MATERIAL AND METHODS In this study, we combined the class III antiarrhythmic agent amiodarone and the BH3 mimetic ABT-263 based on data from a prior drug screen to assess the degree of apoptotic induction in 2 human leukemia cell lines. RESULTS The combination yielded statistically significant increases in apoptosis in both cell lines by downregulating AKT activity and increasing cleaved caspase-3. CONCLUSIONS Overall, our findings suggest that combining K+ channel blockers with prosurvival Bcl-2 family inhibitors is a promising therapeutic approach in treating leukemia.
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Affiliation(s)
- Corey J Ketchem
- Department of Medicine, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky
| | - Cory Kucera
- Department of Physiology, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky
| | - Aditya Barve
- Department of Pharmacology and Toxicology, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky
| | - Levi J Beverly
- Department of Medicine, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky; Department of Physiology, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky; Department of Pharmacology and Toxicology, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky
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The combined activation of K Ca3.1 and inhibition of K v11.1/hERG1 currents contribute to overcome Cisplatin resistance in colorectal cancer cells. Br J Cancer 2017; 118:200-212. [PMID: 29161243 PMCID: PMC5785745 DOI: 10.1038/bjc.2017.392] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2017] [Revised: 09/25/2017] [Accepted: 10/02/2017] [Indexed: 02/06/2023] Open
Abstract
Background: Platinum-based drugs such as Cisplatin are commonly employed for cancer treatment. Despite an initial therapeutic response, Cisplatin treatment often results in the development of chemoresistance. To identify novel approaches to overcome Cisplatin resistance, we tested Cisplatin in combination with K+ channel modulators on colorectal cancer (CRC) cells. Methods: The functional expression of Ca2+-activated (KCa3.1, also known as KCNN4) and voltage-dependent (Kv11.1, also known as KCNH2 or hERG1) K+ channels was determined in two CRC cell lines (HCT-116 and HCT-8) by molecular and electrophysiological techniques. Cisplatin and several K+ channel modulators were tested in vitro for their action on K+ currents, cell vitality, apoptosis, cell cycle, proliferation, intracellular signalling and Platinum uptake. These effects were also analysed in a mouse model mimicking Cisplatin resistance. Results: Cisplatin-resistant CRC cells expressed higher levels of KCa3.1 and Kv11.1 channels, compared with Cisplatin-sensitive CRC cells. In resistant cells, KCa3.1 activators (SKA-31) and Kv11.1 inhibitors (E4031) had a synergistic action with Cisplatin in triggering apoptosis and inhibiting proliferation. The effect was maximal when KCa3.1 activation and Kv11.1 inhibition were combined. In fact, similar results were produced by Riluzole, which is able to both activate KCa3.1 and inhibit Kv11.1. Cisplatin uptake into resistant cells depended on KCa3.1 channel activity, as it was potentiated by KCa3.1 activators. Kv11.1 blockade led to increased KCa3.1 expression and thereby stimulated Cisplatin uptake. Finally, the combined administration of a KCa3.1 activator and a Kv11.1 inhibitor also overcame Cisplatin resistance in vivo. Conclusions: As Riluzole, an activator of KCa3.1 and inhibitor of Kv11.1 channels, is in clinical use, our results suggest that this compound may be useful in the clinic to improve Cisplatin efficacy and overcome Cisplatin resistance in CRC.
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Fortunato A. The role of hERG1 ion channels in epithelial-mesenchymal transition and the capacity of riluzole to reduce cisplatin resistance in colorectal cancer cells. Cell Oncol (Dordr) 2017; 40:367-378. [DOI: 10.1007/s13402-017-0328-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/11/2017] [Indexed: 01/08/2023] Open
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Becchetti A, Crescioli S, Zanieri F, Petroni G, Mercatelli R, Coppola S, Gasparoli L, D'Amico M, Pillozzi S, Crociani O, Stefanini M, Fiore A, Carraresi L, Morello V, Manoli S, Brizzi MF, Ricci D, Rinaldi M, Masi A, Schmidt T, Quercioli F, Defilippi P, Arcangeli A. The conformational state of hERG1 channels determines integrin association, downstream signaling, and cancer progression. Sci Signal 2017; 10:10/473/eaaf3236. [PMID: 28377405 DOI: 10.1126/scisignal.aaf3236] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Ion channels regulate cell proliferation, differentiation, and migration in normal and neoplastic cells through cell-cell and cell-extracellular matrix (ECM) transmembrane receptors called integrins. K+ flux through the human ether-à-go-go-related gene 1 (hERG1) channel shapes action potential firing in excitable cells such as cardiomyocytes. Its abundance is often aberrantly high in tumors, where it modulates integrin-mediated signaling. We found that hERG1 interacted with the β1 integrin subunit at the plasma membrane of human cancer cells. This interaction was not detected in cardiomyocytes because of the presence of the hERG1 auxiliary subunit KCNE1 (potassium voltage-gated channel subfamily E regulatory subunit 1), which blocked the β1 integrin-hERG1 interaction. Although open hERG1 channels did not interact as strongly with β1 integrins as did closed channels, current flow through hERG1 channels was necessary to activate the integrin-dependent phosphorylation of Tyr397 in focal adhesion kinase (FAK) in both normal and cancer cells. In immunodeficient mice, proliferation was inhibited in breast cancer cells expressing forms of hERG1 with impaired K+ flow, whereas metastasis of breast cancer cells was reduced when the hERG1/β1 integrin interaction was disrupted. We conclude that the interaction of β1 integrins with hERG1 channels in cancer cells stimulated distinct signaling pathways that depended on the conformational state of hERG1 and affected different aspects of tumor progression.
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Affiliation(s)
- Andrea Becchetti
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milano, Italy
| | - Silvia Crescioli
- Department of Experimental and Clinical Medicine, University of Firenze, Viale G.B. Morgagni 50, 50134 Firenze, Italy
| | - Francesca Zanieri
- Department of Experimental and Clinical Medicine, University of Firenze, Viale G.B. Morgagni 50, 50134 Firenze, Italy
| | - Giulia Petroni
- Department of Experimental and Clinical Medicine, University of Firenze, Viale G.B. Morgagni 50, 50134 Firenze, Italy
| | - Raffaella Mercatelli
- Consiglio Nazionale delle Ricerche-Istituto Nazionale di Ottica, Via N. Carrara 1, 50019 Sesto Fiorentino, Italy
| | - Stefano Coppola
- Physics of Life Processes, Huygens-Kamerlingh Onnes Laboratory, Leiden University, Niels Bohrweg 2, 2333 CA Leiden, Netherlands
| | - Luca Gasparoli
- Department of Experimental and Clinical Medicine, University of Firenze, Viale G.B. Morgagni 50, 50134 Firenze, Italy
| | - Massimo D'Amico
- Di.V.A.L. Toscana SRL, Via Madonna del Piano 6, 50019 Sesto Fiorentino, Italy
| | - Serena Pillozzi
- Department of Experimental and Clinical Medicine, University of Firenze, Viale G.B. Morgagni 50, 50134 Firenze, Italy
| | - Olivia Crociani
- Department of Experimental and Clinical Medicine, University of Firenze, Viale G.B. Morgagni 50, 50134 Firenze, Italy
| | - Matteo Stefanini
- Di.V.A.L. Toscana SRL, Via Madonna del Piano 6, 50019 Sesto Fiorentino, Italy
| | - Antonella Fiore
- Department of Experimental and Clinical Medicine, University of Firenze, Viale G.B. Morgagni 50, 50134 Firenze, Italy
| | - Laura Carraresi
- Di.V.A.L. Toscana SRL, Via Madonna del Piano 6, 50019 Sesto Fiorentino, Italy
| | - Virginia Morello
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, 10126 Torino, Italy
| | - Sagar Manoli
- Department of Experimental and Clinical Medicine, University of Firenze, Viale G.B. Morgagni 50, 50134 Firenze, Italy
| | - Maria Felice Brizzi
- Department of Medical Sciences, University of Torino, Corso Dogliotti 14, 10126 Torino, Italy
| | - Davide Ricci
- Department of Surgical Sciences, University of Torino, Corso Dogliotti 14, 10126 Torino, Italy
| | - Mauro Rinaldi
- Department of Surgical Sciences, University of Torino, Corso Dogliotti 14, 10126 Torino, Italy
| | - Alessio Masi
- Department of Experimental and Clinical Medicine, University of Firenze, Viale G.B. Morgagni 50, 50134 Firenze, Italy
| | - Thomas Schmidt
- Physics of Life Processes, Huygens-Kamerlingh Onnes Laboratory, Leiden University, Niels Bohrweg 2, 2333 CA Leiden, Netherlands
| | - Franco Quercioli
- Consiglio Nazionale delle Ricerche-Istituto Nazionale di Ottica, Via N. Carrara 1, 50019 Sesto Fiorentino, Italy
| | - Paola Defilippi
- Physics of Life Processes, Huygens-Kamerlingh Onnes Laboratory, Leiden University, Niels Bohrweg 2, 2333 CA Leiden, Netherlands
| | - Annarosa Arcangeli
- Department of Experimental and Clinical Medicine, University of Firenze, Viale G.B. Morgagni 50, 50134 Firenze, Italy.
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Wang L, Xu Z, Chen B, He W, Hu J, Zhang L, Liu X, Chen F. The Role of Vascular Endothelial Growth Factor in Small-airway Remodelling in a Rat Model of Chronic Obstructive Pulmonary Disease. Sci Rep 2017; 7:41202. [PMID: 28117425 PMCID: PMC5259712 DOI: 10.1038/srep41202] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Accepted: 12/16/2016] [Indexed: 11/08/2022] Open
Abstract
Small-airway remodelling is one of the most remarkable pathological features of chronic obstructive pulmonary disease (COPD), in which angiogenesis plays a critical role that contributes to disease progression. The endothelial cell-specific mitogen vascular endothelial growth factor (VEGF), as well as its receptors, VEGFR1, VEGFR2, are thought to be the major mediators of pathological angiogenesis, and sunitinib exhibits anti-angiogenesis property through VEGF blockage and has been widely used to treat various cancers. In our study, Sprague-Dawley rats were subjected to lipopolysaccharide (LPS) injection and cigarette smoke (CS) inhalation to induce COPD, following sunitinib administration was conducted. Haematoxylin-eosin, Masson staining and immunostaining analysis were used to evaluate the pathological changes; quantitative real-time PCR and enzyme-linked immunosorbent assay were performed to provide more compelling data on the function of VEGF, VEGFR1, VEGFR2 in angiogenesis. Sunitinib treatment was associated with less angiogenesis in small-airway remodelling with a slightly disordered lung architecture, and lower expression level of VEGF, VEGFR1, VEGFR2. Overall, our results indicate that VEGF is a vital important factor that contributes to the small-airway remodelling in a rat model of COPD through promoting angiogenesis, which mainly depend on the specific binding between VEGF and VEGFR1 and can be effectively attenuated by sunitinib.
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Affiliation(s)
- Lu Wang
- Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China
| | - Zhibo Xu
- Department of respiration, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310006, People’s Republic of China
| | - Bin Chen
- Respiratory physiology Laboratory, The First Affiliated Hospital of Zhejiang Chinese Medical University, 310006, People’s Republic of China
| | - Wei He
- Department of respiration, Shaoxing Hospital of Traditional Chinese Medicine, Shaoxing, 312000, People’s Republic of China
| | - Jingxian Hu
- Department of respiration, Dongyang Hospital of Traditional Chinese Medicine, Jinhua, 322100, People’s Republic of China
| | - Liting Zhang
- Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China
| | - Xianzhong Liu
- Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China
| | - Fang Chen
- Respiratory physiology Laboratory, The First Affiliated Hospital of Zhejiang Chinese Medical University, 310006, People’s Republic of China
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Soriani O, Rapetti-Mauss R. Sigma 1 Receptor and Ion Channel Dynamics in Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 964:63-77. [PMID: 28315265 DOI: 10.1007/978-3-319-50174-1_6] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
SigmaR1 is a multitasking chaperone protein which has mainly been studied in CNS physiological and pathophysiological processes such as pain, memory, neurodegenerative diseases (amyotrophic lateral sclerosis , Parkinson's and Alzheimer's diseases, retinal neurodegeneration ), stroke and addiction . Strikingly, G-protein and ion channels are the main client protein fami lies of this atypical chaperone and the recent advances that have been performed for the last 10 years demonstrate that SigmaR1 is principally activated following tissue injury and disease development to promote cell survival. In this chapter, we synthesize the data enhancing our comprehension of the interaction between SigmaR1 and ion channels and the unexpected consequences of such functional coupling in cancer development. We also describe a model in which the pro-survival functions of SigmaR1 observed in CNS pathologies are hijacked by cancer cells to shape their electrical signature and behavior in response to the tumor microenvironment .
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Affiliation(s)
- Olivier Soriani
- University of Nice Sophia Antipolis, CNRS, Inserm, iBV, 06108, Nice, France.
- Bâtiment Sciences Naturelles; UFR Sciences, 06108, Nice, France.
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Muratori L, Petroni G, Antonuzzo L, Boni L, Iorio J, Lastraioli E, Bartoli G, Messerini L, Di Costanzo F, Arcangeli A. hERG1 positivity and Glut-1 negativity identifies high-risk TNM stage I and II colorectal cancer patients, regardless of adjuvant chemotherapy. Onco Targets Ther 2016; 9:6325-6332. [PMID: 27789963 PMCID: PMC5072508 DOI: 10.2147/ott.s114090] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND The identification of early-stage colorectal cancer (CRC) with high risk of progression is one major clinical challenge, mainly due to lack of validated biomarkers. The aims of the present study were to analyze the prognostic impact of three molecular markers belonging to the ion channels and transporters family: the ether-à-go-go-related gene 1 (hERG1) and the calcium-activated KCa3.1 potassium channels, as well as the glucose transporter 1 (Glut-1); and to define the impact of adjuvant chemotherapy in conjunction with the abovementioned biomarkers, in a cohort of radically resected stage I-III CRC patients. PATIENTS AND METHODS The expressions of hERG1, KCa3.1, and Glut-1 were tested by immunohistochemistry on 162 surgical samples of nonmetastatic, stage I-III CRC patients. The median follow-up was 32 months. The association between biological markers, clinicopathological features, and survival outcomes was investigated by evaluating both disease-free survival and overall survival. RESULTS Although no prognostic valence emerged for KCa3.1, evidence of a negative impact of hERG1 expression on survival outcomes was provided. On the contrary, Glut-1 expression had a positive impact. According to the results of the multivariate analysis, patients were stratified in four risk groups, based on TNM stage and hERG1/Glut-1 expression. After adjusting for adjuvant therapy, stage I and II, Glut-1-negative, and hERG1-positive patients showed the worst survival experience. CONCLUSION This study strongly indicates that the combination of hERG1 positivity and Glut-1 negativity behaves as a prognostic biomarker in radically resected CRC patients. This combination identifies a group of stage I and II CRC patients with a bad prognosis, even worse than that of stage III patients, regardless of adjuvant therapy accomplishment.
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Affiliation(s)
- Leonardo Muratori
- Department of Experimental and Clinical Medicine, University of Florence
| | - Giulia Petroni
- Department of Experimental and Clinical Medicine, University of Florence
| | - Lorenzo Antonuzzo
- Medical Oncology, Azienda Ospedaliero-Universitaria Careggi, Florence; Department of Medical Biotechnologies, University of Siena, Siena
| | - Luca Boni
- Clinical Trials Coordinating Center, Istituto Toscano Tumori, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy
| | - Jessica Iorio
- Department of Experimental and Clinical Medicine, University of Florence; Department of Medical Biotechnologies, University of Siena, Siena
| | - Elena Lastraioli
- Department of Experimental and Clinical Medicine, University of Florence
| | - Gianluca Bartoli
- Department of Experimental and Clinical Medicine, University of Florence
| | - Luca Messerini
- Department of Experimental and Clinical Medicine, University of Florence
| | | | - Annarosa Arcangeli
- Department of Experimental and Clinical Medicine, University of Florence
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50
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Pointer KB, Clark PA, Eliceiri KW, Salamat MS, Robertson GA, Kuo JS. Administration of Non-Torsadogenic human Ether-à-go-go-Related Gene Inhibitors Is Associated with Better Survival for High hERG-Expressing Glioblastoma Patients. Clin Cancer Res 2016; 23:73-80. [PMID: 27635088 DOI: 10.1158/1078-0432.ccr-15-3169] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Revised: 08/12/2016] [Accepted: 09/03/2016] [Indexed: 12/29/2022]
Abstract
PURPOSE Glioblastoma is the most malignant primary brain tumor, with a median survival of less than 2 years. More effective therapeutic approaches are needed to improve clinical outcomes. EXPERIMENTAL DESIGN Glioblastoma patient-derived cells (GPDC) were isolated from patient glioblastomas and implanted in mice to form xenografts. IHC was performed for human Ether-à-go-go-Related Gene (hERG) expression and tumor proliferation. Sphere-forming assays with the hERG blocker E-4031 were performed on a high and low hERG-expressing lines. A glioblastoma tissue microarray (TMA; 115 patients) was used to correlate hERG expression with patient survival. Clinical data were analyzed to determine whether patient survival was affected by incidental administration of hERG inhibitory drugs and the correlative effect of patient glioblastoma hERG expression levels. RESULTS hERG expression was upregulated in glioblastoma xenografts with higher proliferative indices. High hERG-expressing GPDCs showed a reduction in sphere formation when treated with hERG inhibitors compared with low hERG-expressing GPDCs. Glioblastoma TMA analysis showed worse survival for glioblastoma patients with high hERG expression versus low expression-43.5 weeks versus 60.9 weeks, respectively (P = 0.022). Furthermore, patients who received at least one hERG blocker had a better survival rate compared with patients who did not (P = 0.0015). Subgroup analysis showed that glioblastoma patients with high hERG expression who received hERG blockers had improved survival (P = 0.0458). There was no difference in survival for low hERG-expressing glioblastoma patients who received hERG blockers (P = 0.4136). CONCLUSIONS Our findings suggest that hERG is a potential glioblastoma survival marker, and that already approved drugs with non-torsadogenic hERG inhibitory activity may potentially be repurposed as adjuvant glioblastoma therapy in high hERG-expressing glioblastoma patients. Clin Cancer Res; 23(1); 73-80. ©2016 AACRSee related commentary by Arcangeli and Becchetti, p. 3.
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Affiliation(s)
- Kelli B Pointer
- Department of Neurological Surgery, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin.,Medical Scientist Training Program, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin.,Cellular and Molecular Biology, University of Wisconsin-Madison, Madison, Wisconsin.,Laboratory for Optical and Computational Instrumentation (LOCI), University of Wisconsin-Madison, Madison, Wisconsin
| | - Paul A Clark
- Department of Neurological Surgery, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin
| | - Kevin W Eliceiri
- Laboratory for Optical and Computational Instrumentation (LOCI), University of Wisconsin-Madison, Madison, Wisconsin.,Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin
| | - M Shahriar Salamat
- Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, Wisconsin
| | - Gail A Robertson
- Department of Neuroscience, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin. .,Cardiovascular Research Center, University of Wisconsin-Madison, Madison, Wisconsin
| | - John S Kuo
- Department of Neurological Surgery, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin. .,Medical Scientist Training Program, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin.,Cellular and Molecular Biology, University of Wisconsin-Madison, Madison, Wisconsin.,Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin.,Department of Surgery, National University of Singapore, Singapore
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