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Targeting a mitochondrial potassium channel to fight cancer
•Potassium channels are expressed in the inner mitochondrial membrane.•Mitochondrial potassium channels are important in the regulation of mitochondrial energetics.•Mitochondrial potassium channels are central in the regulation of cell death.•Mitochondrial Kv1.3 binds to Bax and Bak proteins that in...
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Published in: | Cell calcium (Edinburgh) 2015-07, Vol.58 (1), p.131-138 |
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Main Authors: | , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | •Potassium channels are expressed in the inner mitochondrial membrane.•Mitochondrial potassium channels are important in the regulation of mitochondrial energetics.•Mitochondrial potassium channels are central in the regulation of cell death.•Mitochondrial Kv1.3 binds to Bax and Bak proteins that inhibit Kv1.3 by a toxin like mechanism.•Inhibition of mitochondrial Kv1.3 can be achieved by drugs to treat human malignancies.
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. |
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ISSN: | 0143-4160 1532-1991 |
DOI: | 10.1016/j.ceca.2014.09.006 |