Neonatal Nav1.5 protein expression in normal adult human tissues and breast cancer

Yamaci, Rezan Fahrioglu; Fraser, Scott P.; Battaloğlu, Esra; Kaya, Hakan; Erguler, Kamil; Foster, Christopher S.; Djamgoz, Mustafa B.A.

doi:10.1016/j.prp.2017.06.003

Cited by 34 publications

(37 citation statements)

References 47 publications

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“…Third , the predominant VGSC in cancers of breast and colon is the neonatal splice variant of Nav1.5 (nNav1.5) ( 185 , 186 ). This offers several advantages as a target, including having an extracellular region that can be targeted by an antibody and a restricted expression pattern in the adult human body ( 187 , 188 ). Accordingly, nNav1.5 exprssion may be cancer-specific and could form the basis of CAR-T immunotherapy.…”

Section: Potential Novel Immunotherapy Co-targetsmentioning

confidence: 99%

Immuno-Oncology: Emerging Targets and Combination Therapies

2018

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Host immunity recognizes and eliminates most early tumor cells, yet immunological checkpoints, exemplified by CTLA-4, PD-1, and PD-L1, pose a significant obstacle to effective antitumor immune responses. T-lymphocyte co-inhibitory pathways influence intensity, inflammation and duration of antitumor immunity. However, tumors and their immunosuppressive microenvironments exploit them to evade immune destruction. Recent PD-1 checkpoint inhibitors yielded unprecedented efficacies and durable responses across advanced-stage melanoma, showcasing potential to replace conventional radiotherapy regimens. Neverthless, many clinical problems remain in terms of efficacy, patient-to-patient variability, and undesirable outcomes and side effects. In this review, we evaluate recent advances in the immuno-oncology field and discuss ways forward. First, we give an overview of current immunotherapy modalities, involving mainy single agents, including inhibitor monoclonal antibodies (mAbs) targeting T-cell checkpoints of PD-1 and CTLA-4. However, neoantigen recognition alone cannot eliminate tumors effectively in vivo given their inherent complex micro-environment, heterogeneous nature and stemness. Then, based mainly upon CTLA-4 and PD-1 checkpoint inhibitors as a “backbone,” we cover a range of emerging (“second-generation”) therapies incorporating other immunotherapies or non-immune based strategies in synergistic combination. These include targeted therapies such as tyrosine kinase inhibitors, co-stimulatory mAbs, bifunctional agents, epigenetic modulators (such as inhibitors of histone deacetylases or DNA methyltransferase), vaccines, adoptive-T-cell therapy, nanoparticles, oncolytic viruses, and even synthetic “gene circuits.” A number of novel immunotherapy co-targets in pre-clinical development are also introduced. The latter include metabolic components, exosomes and ion channels. We discuss in some detail of the personalization of immunotherapy essential for ultimate maximization of clinical outcomes. Finally, we outline possible future technical and conceptual developments including realistic in vitro and in vivo models and inputs from physics, engineering, and artificial intelligence. We conclude that the breadth and quality of immunotherapeutic approaches and the types of cancers that can be treated will increase significantly in the foreseeable future.

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Section: Potential Novel Immunotherapy Co-targetsmentioning

confidence: 99%

Immuno-Oncology: Emerging Targets and Combination Therapies

2018

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“…In this regard, a recent study has reported that high Nav1.5 expression levels correlated with unfavorable disease-free survival in patients with nonmetastatic CRC [162]. Second, as a neonatal splice variant, it has the potential to be 'cancer specific' in the adult body [163]. It can be targeted with antibody, therefore, both for diagnosis and therapy.…”

Section: P53 Pathway In Colorectal Cancermentioning

confidence: 99%

Overview of the oncogenic signaling pathways in colorectal cancer: Mechanistic insights

Farooqı

Djamgoz

Siddik

2019

Seminars in Cancer Biology

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111

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Colorectal cancer is a multifaceted disease which is therapeutically challenging. Based on insights gleaned from decades of research, it seems clear that deregulation of spatio-temporally controlled signaling pathways play instrumental role in development and progression of colorectal cancer. Highthroughput technologies have helped to develop a sharper and broader understanding of the wide ranging signal transduction cascades which also contribute to development of drug resistance, loss of apoptosis and, ultimately, of metastasis. In this review, we have set the spotlight on role of JAK/STAT, TGF/SMAD, Notch, WNT/β-Catenin, SHH/GLI and p53 pathways in the development and progression of colorectal cancer. We have also highlighted recent reports on TRAIL-mediated pathways and molecularly distinct voltage-gated sodium channels in colorectal cancer. Introduction: Colorectal cancer is the 3 rd commonest cancer and the 2 nd leading cause of cancer-related deaths in the Western world (1). The outlook for disease incidence rates is bleak, reports predict up to a 60% rise in the global burden of CRC in developing countries by 2030 (2). Innovations in disease management are critical. Serine-20, may be less effective at mediating p53-dependent antitumor effects in these specific colorectal cancer patients. To our knowledge, such an investigation has not been reported as yet. Voltage-gated ion (sodium) channel expression in colorectal cancer: The bioelectricity of cancer cells generally differs from normal cells in several different respects [147]. In particular, increasing evidence suggest that a variety of ion channels, including voltage-gated ion channels, play a significant, dynamic role in the pathophysiology of cancer, including CRC [148]. Virtually all types of ion channel are involved, contributing to different components / stages of the cancer process. These include voltage-gated Na + , K +, Ca 2+ and Clchannels, ligand-gated ion channels and 'transient receptor potential' (Trp) channels [148]. Thus, cancer may even be regarded as a 'channelopathy' [148]. Here we focus on ion channels involved in metastasis since this is the main cause of death from cancer including CRC. In this regard, it is that has received the most attention [149]. According to the "Celex Hypothesis", acquisition of metastatic potential in cancer cells involves upregulation of functional voltage-gated Na + channels (VGSCs) activity and concomitant downregulation of outward currents, driven at least in part by voltage-gated K + channels (VGPCs) [150]. Overall, the possible electrical 'excitability' could form the basis of aggressive cancer cell behavior [150]. Membrane and protease genes Wnt signaling MAPK signaling Calcium signaling Membrane remodelling or secretion SCN5A Tumor cell invasion

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“…Nav1.5 in its neonatal DI:S3 5′ splice form is predominantly expressed in metastatic cancer cells (Fraser et al, 2005;Yamaci et al, 2017). This form has been found to participate in neonatal development, while it is absent in postnatal development.…”

Section: Nav15 Expression and Its Functional Role In Breast Cancer Mmentioning

confidence: 99%

“…Nelson and his colleagues investigated the functional activity of Nav1.5 and its specific contribution to breast cancer tumor progression. SCN5A is upregulated at the mRNA and protein levels in metastatic breast tumors compared to that in normal, non-cancerous tissue (Nelson et al, 2015a;Nelson et al, 2015b;Yamaci et al, 2017) Furthermore, some factors affect Nav1.5 expression in breast cancer cells. The b1 subunit mRNA and protein are strongly expressed in MCF-7 cells and are barely detectable in MDA-MB-231 cells.…”

Section: Nav15 Expression and Its Functional Role In Breast Cancer Mmentioning

confidence: 99%

“…Aberrant expression and activity of Nav1.5 are associated with cardiac excitability diseases such as arrhythmic dilated cardiomyopathy, Brugada syndrome, and long QT syndrome (Antzelevitch et al, 2005;Amin et al, 2013;Giudicessi and Ackerman, 2013;Beckermann et al, 2014). Nav1.5 is also overexpressed in metastatic breast cancer in vitro and in vivo and mainly exists in its DI: S3 5′ neonatal splice form (nNav1.5) in breast cancer cells, potentiating cell metastasis (Mohammed et al, 2016;Yamaci et al, 2017). Breast cancer cells treated with specific Nav1.5 inhibitors or siRNAs show decreased motility and metastatic capacity (Driffort et al, 2014).Therefore, Nav1.5 may be regarded as a promising target for the diagnosis and therapy of breast cancer.…”

Section: Introductionmentioning

confidence: 99%

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The Functional Role of Voltage-Gated Sodium Channel Nav1.5 in Metastatic Breast Cancer

Luo

et al. 2020

Front. Pharmacol.

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Voltage-gated sodium channels (VGSCs), which are abnormally expressed in various types of cancers such as breast cancer, prostate cancer, lung cancer, and cervical cancer, are involved in the metastatic process of invasion and migration. Nav1.5 is a poreforming a subunit of VGSC encoded by SCN5A. Various studies have demonstrated that Nav1.5, often as its neonatal splice form, is highly expressed in metastatic breast cancer cells. Abnormal activation and expression of Nav1.5 trigger a variety of cellular mechanisms, including changing H + efflux, promoting epithelial-to-mesenchymal transition (EMT) and the expression of cysteine cathepsin, to potentiate the metastasis and invasiveness of breast cancer cells in vitro and in vivo. Here, we systematically review the latest available data on the pro-metastatic effect of Nav1.5 and its underlying mechanisms in breast cancer. We summarize the factors affecting Nav1.5 expression in breast cancer cells, and discuss the potential of Nav1.5 blockers serving as candidates for breast cancer treatment.

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Neonatal Nav1.5 protein expression in normal adult human tissues and breast cancer

Cited by 34 publications

References 47 publications

Immuno-Oncology: Emerging Targets and Combination Therapies

Immuno-Oncology: Emerging Targets and Combination Therapies

Overview of the oncogenic signaling pathways in colorectal cancer: Mechanistic insights

The Functional Role of Voltage-Gated Sodium Channel Nav1.5 in Metastatic Breast Cancer

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