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Catenin Signaling Pathway in Cancers Raphaël Rapetti-Mauss, Camille Berenguier, Benoit Allegrini, Olivier Soriani

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Catenin Signaling Pathway in Cancers Raphaël Rapetti-Mauss, Camille Berenguier, Benoit Allegrini, Olivier Soriani Interplay Between Ion Channels and the Wnt/β-Catenin Signaling Pathway in Cancers Raphaël Rapetti-Mauss, Camille Berenguier, Benoit Allegrini, Olivier Soriani To cite this version: Raphaël Rapetti-Mauss, Camille Berenguier, Benoit Allegrini, Olivier Soriani. Interplay Between Ion Channels and the Wnt/β-Catenin Signaling Pathway in Cancers. Frontiers in Pharmacology, Frontiers, 2020, 11, 10.3389/fphar.2020.525020. hal-03059067 HAL Id: hal-03059067 https://hal.archives-ouvertes.fr/hal-03059067 Submitted on 12 Dec 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. REVIEW published: 29 September 2020 doi: 10.3389/fphar.2020.525020 Interplay Between Ion Channels and the Wnt/b-Catenin Signaling Pathway in Cancers Raphael Rapetti-Mauss*, Camille Berenguier, Benoit Allegrini and Olivier Soriani Inserm, CNRS, iBV, Universite´ Coˆ te d’Azur, Nice, France Increasing evidence point out the important roles of ion channels in the physiopathology of cancers, so that these proteins are now considered as potential new therapeutic targets and biomarkers in this disease. Indeed, ion channels have been largely described to participate in many hallmarks of cancers such as migration, invasion, proliferation, angiogenesis, and resistance to apoptosis. At the molecular level, the development of cancers is characterised by alterations in transduction pathways that control cell Edited by: behaviors. However, the interactions between ion channels and cancer-related Se´ bastien Roger, signaling pathways are poorly understood so far. Nevertheless, a limited number of Universite´ de Tours, France reports have recently addressed this important issue, especially regarding the interaction Reviewed by: between ion channels and one of the main driving forces for cancer development: the Irene Frischauf, b Johannes Kepler University of Linz, Wnt/ -catenin signaling pathway. In this review, we propose to explore and discuss the Austria current knowledge regarding the interplay between ion channels and the Wnt/b-catenin Heike Wulff, signaling pathway in cancers. University of California, Davis, United States Keywords: signaling pathways, drug targets, KCNQ1 channel, P2X7, cystic fibrosis transmembrane conductance *Correspondence: regulator, hERG, transient receptor protein channels, ClC-2 channel Raphael Rapetti-Mauss Raphael.RAPETTI-MAUSS@univ- cotedazur.fr INTRODUCTION Specialty section: This article was submitted to Despite decades of intensive research on its physiopathology, cancer remains a leading cause of Pharmacology of Ion Channels death worldwide according to the World Health Organisation. Traditional cancer treatments and Channelopathies, including radiation therapy, chemotherapy, and surgery have substantially improved patients’ a section of the journal conditions. However, several challenges in curing cancer remain in front of us. Side effects generated Frontiers in Pharmacology by cancer treatments significantly impact patients quality of life; high patients intrinsic Received: 07 January 2020 heterogeneity revealed treatments resistance, and finally the efficiency of treatment used for some Accepted: 31 August 2020 types of cancer remains very low such as for pancreatic cancer. These circumstances highlight the Published: 29 September 2020 urgent need to identify new therapeutic strategies in treating cancers. Citation: Ion channels are transmembrane proteins allowing ions to cross biological membranes thereby Rapetti-Mauss R, Berenguier C, generating electrical current and variation in membrane potential. Ion channels are classified in five Allegrini B and Soriani O (2020) main families, Potassium channels, Chloride channels, Sodium channels, Calcium channels that are Interplay Between Ion Channels fi b selective for their speci c ion, and non-selective ion channels that allow the passage of several and the Wnt/ -Catenin Signaling fi fi Pathway in Cancers. species of ions. The functions attributed to ion channels were rst con ned to cell excitability and Front. Pharmacol. 11:525020. regulation of hydro-electrolytic balance. Interestingly, since the 1980’s ion channels have also been doi: 10.3389/fphar.2020.525020 described to be involved in controlling processes regulating cell behaviors such as proliferation, Frontiers in Pharmacology | www.frontiersin.org1 September 2020 | Volume 11 | Article 525020 Rapetti-Mauss et al. Ion Channels and Wnt Signaling migration, invasion and differentiation. In 1984, the pioneer secreted, Wnt ligands can form a gradient and act as work of DeCoursey describing the involvement of potassium directional growth factor, as it is the case in intestinal colonic channels in the proliferation of T lymphocytes (DeCoursey et al., crypts (Medema and Vermeulen, 2011) 1984) opened new perspectives in studying the biology of ion Here we will focus on Wnt canonical pathway, which depends channels. The first evidence for such functions of ion channels in on b-catenin stability. In the absence of Wnt ligand (Wnt OFF cancer cells emerged in the late 1980’s with studies describing state), cytosolic b-catenin is sequestrated by a destruction that the pharmacological inhibition of ion channels reduces complex (DC) composed of the tumor suppressor Axin acting tumor cells proliferation (Yamashita et al., 1987; Lee et al., as scaffold protein, the tumor suppressor Adenomatous 1988; Pancrazio et al., 1989; Taylor and Simpson, 1992). Since Polyposis Coli (APC), the glycogen synthase kinase 3b then, the field has greatly expanded, and it has been shown that (GSK3b) and casein kinase 1a (CK1a). Inside this DC, b- ion channels are involved in virtually all the hallmarks of cancers catenin is bound to Axin and phosphorylated by the two described by Hanahan et al. (Prevarskaya et al., 2010; constitutively active kinases GSK3b and CK1a at specific Prevarskaya et al., 2018). Although the involvement of ion Serine and Threonine residues (Liu et al., 2002). Then, b- channels in cancer has been clearly described, how ion catenin is ubiquitylated by the F-box containing protein E3 channels interact with cancer-related signaling pathways from ubiquitin ligase (b-TrCP) and addressed to the proteasome for a mechanistic point of view, and how the expression of ion degradation (Aberle et al., 1997; Latres et al., 1999). channels is regulated in cancers is poorly understood. However, Initiation of the Wnt canonical (b-catenin-dependent) this issue has recently emerged in the literature and a growing pathway (Wnt ON state) is mediated by engagement of number of reports tackle these questions. Cancer initiation and Frizzled (Fz) receptor and LRP5/6 co-receptor with Wnt development is often associated to altered signaling pathway ligands. Activation of the pathway leads to degradation involved in cell and tissue homeostasis (Sanchez-Vega et al., complex relocation near Fz/LRP complexes, where LRP is 2018). Among these signaling pathways, the Wnt/b-catenin phosphorylated by CK1a and GSK3b. The phosphorylation of pathway emerged as the most associated pathway to ion LRP triggers Dishevelled (Dvl) protein polymerisation, thus channels in the literature. This review aims to summarize the inactivating the degradation complex (Metcalfe et al., 2010). current knowledge regarding the interplay between ion channels Another study suggests a direct inhibition of GSK3b by the and the Wnt/b-catenin signaling pathway. phosphorylated-LRP co-receptor (Stamos et al., 2014). Hence, b- catenin is not degraded, can accumulate in the cytoplasm and translocate into the nucleus. b-catenin then complexes with THE WNT SIGNALING PATHWAY lymphoid enhanced factor (LEF) and T-cell factor (TCF) to act as a transcription factor activating target genes (Li et al., 2012). In Since the first description of Wingless Int 1 (Wnt1) gene in the Wnt OFF state, TCF interacts with Groucho, preventing virally induced breast tumors (Nusse and Varmus, 1982), the transcriptional activation of Wnt target genes (Cavallo et al., Wnt signaling pathway has been subjected to intense research, 1998). Interestingly, b-catenin plays a second role in maintaining ranging from development to cancer. Its role in morphogenesis epithelial junctions, by binding to the cytoplasmic tail of E- and adult stem cell renewal is closely linked to its involvement in cadherin (Peifer et al., 1992). Thus, presence of epithelial cancer development (Nusse and Clevers, 2017). Mechanistically, junctions is a limiting factor for Wnt/b-catenin activity, and Wnt signaling pathway can take mostly two directions: the reciprocally (Huels et al., 2015). canonical (Wnt/b-catenin), influencing cell-fate, proliferation, The Wnt/b-catenin pathway is tightly regulated. For example, as well as self-renewal and the non-canonical (b-catenin- the two homologues E3 ubiquitin ligases ZNRF3/RNF43 can independent), Wnt/PCP, Wnt/Ca++,Wnt/STOP,influencing induce Fz receptor lysosomal degradation, thus inhibiting Wnt planar polarity (Tree et al., 2002), Ca2+ homeostasis (Sheldahl signaling. R-spondins are secreted proteins, interacting with their et al., 2003), or protein stabilization
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