title: Targeting a mitochondrial potassium channel to fight cancer.
abstract: Although chemotherapy is able to cure many patients with malignancies, it still also often fails. Therefore, novel approaches and targets for chemotherapeutic treatment of malignancies are urgently required. Recent studies demonstrated the expression of several potassium channels in the inner mitochondrial membrane. Among them the voltage gated potassium channel Kv1.3 and the big-potassium (BK) channel were shown to directly function in cell death by serving as target for pro-apoptotic Bax and Bak proteins. Here, we discuss the role of mitochondrial potassium channel Kv1.3 (mitoKv1.3) in cell death and its potential function in treatment of solid tumors, leukemia and lymphoma. Bax and Bak inhibit mitoKv1.3 by directly binding into the pore of the channel, by a toxin-like mechanism. Inhibition of mitoKv1.3 results in an initial hyperpolarization of the inner mitochondrial membrane that triggers the production of reactive oxygen species (ROS). ROS in turn induce a release of cytochrome c from the cristae of the inner mitochondrial membrane and an activation of the permeability transition pore, resulting in opening of the intrinsic apoptotic cell death. Since mitoKv1.3 functions downstream of pro-apoptotic Bax and Bak, compounds that directly inhibit mitoKv1.3 may serve as a new class of drugs for treatment of tumors, even with an altered expression of either pro- or anti-apoptotic Bcl-2 protein family members. This was successfully proven by the in vivo treatment of mouse melanoma and ex vivo human chronic leukemia B cells with inhibitors of mitoKv1.3.
authors.affiliation: Department of Biology, University of Padova, Viale G. Colombo 3, 35131 Padova, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Leanza
authors.affiliation: Department of Molecular Biology, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany.
authors.forename: Elisa
authors.initials: E
authors.lastname: Venturini
authors.affiliation: Department of Molecular Biology, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Kadow
authors.affiliation: Department of Molecular Biology, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Carpinteiro
authors.affiliation: Department of Molecular Biology, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany. Electronic address: erich.gulbins@uni-due.de.
authors.forename: Erich
authors.initials: E
authors.lastname: Gulbins
authors.affiliation: Department of Molecular Biology, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany. Electronic address: katrin.becker-flegler@uni-due.de.
authors.forename: Katrin Anne
authors.initials: KA
authors.lastname: Becker
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000627:therapeutic use / Q000633:toxicity; D015221:Potassium Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D026902:Potassium Channel Blockers; D015221:Potassium Channels; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D011188:Potassium
keywords: Bax; Cell death; Mitochondria; Potassium channel; Toxins