Please cite this article in press as: L. Leanza, et al., Targeting a mitochondrial potassium channel to fight cancer, Cell Calcium (2014), http://dx.doi.org/10.1016/j.ceca.2014.09.006 ARTICLE IN PRESS G Model YCECA-1604; No. of Pages 8 Cell Calcium xxx (2014) xxx–xxx Contents lists available at ScienceDirect Cell Calcium jou rn al hom epage: www.elsevier.com/locate/ceca Targeting a mitochondrial potassium channel to fight cancer Luigi Leanza a , Elisa Venturini b , Stephanie Kadow b , Alexander Carpinteiro b , Erich Gulbins b,∗∗ , Katrin Anne Becker b,∗ a Department of Biology, University of Padova, Viale G. Colombo 3, 35131 Padova, Italy b Department of Molecular Biology, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany a r t i c l e i n f o Article history: Received 8 July 2014 Received in revised form 10 September 2014 Accepted 11 September 2014 Available online xxx Keywords: Potassium channel Mitochondria Cell death Bax Toxins a b s t r a c t 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. © 2014 Published by Elsevier Ltd. 1. Introduction Chemotherapeutic drugs target malignant tumors by a variety of mechanisms, including inhibition of proliferation, direct induction of tumor cell death by any form of apoptosis or necrosis, by activa- tion of the immune system and by altering the niche of the tumor, in particular the tumor stem cell niche. Death of tumor cells is an important mechanism to contribute to a successful chemotherapy. Thus, it is of great clinical interest to define molecular mecha- nisms that mediate cell death. Since, unfortunately, chemotherapy still often fails and many patients die, it is also very important to identify novel targets for chemotherapy and, thereby, poten- tial novel chemotherapeutic drugs. Here, we will focus on the role of potassium channel of the Shaker family, Kv1.3, in mitochon- dria (mitoKv1.3), its role in apoptosis and its potential function as targets in chemotherapy. ∗ Corresponding author. Tel.: +49 201 723 1949; fax: +49 201 723 5974. ∗∗ Corresponding author. Tel.: +49 201 723 3118; fax: +49 201 723 5974. E-mail addresses: erich.gulbins@uni-due.de (E. Gulbins), katrin.becker-flegler@uni-due.de (K.A. Becker). Mitochondria are in the center of many pathways that induce apoptosis or necrosis [1,2]. Death receptors, but also exogenous stress stimuli such as irradiation, converge to the activation of the pro-apoptotic Bcl-2 family proteins Bax and Bak. The critical role of Bax and Bak in apoptosis has been shown in numerous studies (for a recent review see Ref. [3]). Activation of Bax by pro-apoptotic stimuli results in its translocation and integration into the outer mitochondrial membrane. The molecular details of this process are still unknown. Bak proteins seem to be loosely associated with the outer mito- chondrial membrane [4]. Activation of Bak results in integration of the protein into the outer mitochondrial membrane [4]. Activated Bax assembles in oligomers that seem to form pores although these pores were detected at low pH and their in vivo relevance remains to be established [5–9]. Structural studies indicated that after incor- poration of Bax into the outer mitochondrial membrane, only two amino acids stick out of the outer mitochondrial membrane and face the inner mitochondrial membrane, i.e. amino acids 127 and 128 located between the 5th and 6th helices of Bax [10]. The amino acid at position 128 is a positively charged lysine. However, it is well established that the integration of Bax mediates the release of cytochrome c and other pro-apoptotic molecules such as APAF1 http://dx.doi.org/10.1016/j.ceca.2014.09.006 0143-4160/© 2014 Published by Elsevier Ltd.