title: Chloride channels in cancer: Focus on chloride intracellular channel 1 and 4 (CLIC1 AND CLIC4) proteins in tumor development and as novel therapeutic targets.
abstract: In recent decades, growing scientific evidence supports the role of ion channels in the development of different cancers. Both potassium selective pores and chloride permeabilities are considered the most active channels during tumorigenesis. High rate of proliferation, active migration, and invasiveness into non-neoplastic tissues are specific properties of neoplastic transformation. All these actions require partial or total involvement of chloride channel activity. In this context, this class of membrane proteins could represent valuable therapeutic targets for the treatment of resistant tumors. However, this encouraging premise has not so far produced any valid new channel-targeted antitumoral molecule for cancer treatment. Problematic for drug design targeting ion channels is their vital role in normal cells for essential physiological functions. By targeting these membrane proteins involved in pathological conditions, it is inevitable to cause relevant side effects in healthy organs. In light of this, a new protein family, the chloride intracellular channels (CLICs), could be a promising class of therapeutic targets for its intrinsic individualities: CLIC1 and CLIC4, in particular, not only are overexpressed in specific tumor types or their corresponding stroma but also change localization and function from hydrophilic cytosolic to integral transmembrane proteins as active ionic channels or signal transducers during cell cycle progression in certain cases. These changes in intracellular localization, tissue compartments, and channel function, uniquely associated with malignant transformation, may offer a unique target for cancer therapy, likely able to spare normal cells. This article is part of a special issue itled "Membrane Channels and Transporters in Cancers."
authors.affiliation: Department of Life Science, University of Milan, Milano I-20133, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Peretti
authors.affiliation: Department of Life Science, University of Milan, Milano I-20133, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Angelini
authors.affiliation: Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90075, USA.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Savalli
authors.affiliation: Sezione di Farmacologia, Dipartimento di Medicina Interna and Centro di Eccellenza per la Ricerca Biomedica (CEBR), University of Genova, Genova, Italy.
authors.forename: Tullio
authors.initials: T
authors.lastname: Florio
authors.affiliation: Laboratory of Cancer Biology and Genetics, Center for Cancer Research, NCI, Bethesda, MD 20892, USA.
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Yuspa
authors.affiliation: Department of Life Science, University of Milan, Milano I-20133, Italy. Electronic address: michele.mazzanti@unimi.it.
authors.forename: Michele
authors.initials: M
authors.lastname: Mazzanti
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018118:Chloride Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D049990:Membrane Transport Modulators / Q000627:therapeutic use*; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009928:Organ Specificity; D059016:Tumor Microenvironment / Q000187:drug effects / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; C501966:CLIC1 protein, human; C464459:CLIC4 protein, human; D018118:Chloride Channels; D049990:Membrane Transport Modulators
keywords: CLIC1; CLIC4; Cancer cells; Chloride channels