![]() ![]() ![]() Here we give a brief overview of the contribution of various mitochondrial and other organellar channels to cancer cell proliferation or death. Much attention is focused on channels involved in intracellular calcium signaling and on ion fluxes in the ATP-producing organelle mitochondria. Mitochondrial K + channels (Ca 2+-dependent BK Ca and IK Ca, ATP-dependent K ATP, Kv1.3, two-pore TWIK-related Acid-Sensitive K + channel-3 (TASK-3)), Ca 2+ uniporter MCU, Mg 2+-permeable Mrs2, anion channels (voltage-dependent chloride channel VDAC, intracellular chloride channel CLIC) and the Permeability Transition Pore (MPTP) contribute importantly to the regulation of function in this organelle. Since mitochondria play a central role in apoptosis, modulation of their ion channels by pharmacological means may lead to death of cancer cells. ![]() The nuclear potassium channel Kv10.1 and the nuclear chloride channel CLIC4 as well as the endoplasmatic reticulum (ER)-located inositol 1,4,5-trisphosphate (IP 3) receptor, the ER-located Ca 2+ depletion sensor STIM1 (stromal interaction molecule 1), a component of the store-operated Ca 2+ channel and the ER-resident TRPM8 are also mentioned. Furthermore, pharmacological tools affecting organellar channels and modulating cancer cell survival are discussed. The channels described in this review are summarized on Figure 1. Overall, the view is emerging that intracellular ion channels may represent a promising target for cancer treatment. The “impermeable” mitochondrial inner membrane (IMM) allows the formation of an electrochemical proton gradient which drives the aerobic synthesis of ATP. The “semipermeable” outer membrane (OMM) encloses a periplasmic space where proteins with fundamental roles in cell death are stored until a sufficiently strong pro-apoptotic signal arrives. ![]() Mitochondria have assumed a peculiar role in cancer cell physiology ( Ralph and Neuzil, 2009). They are crucial for the control of intracellular Ca 2+ homeostasis, and produce reactive oxygen species (ROS). ROS are involved in the regulation of physiological processes, but may also be harmful if produced excessively. Mitochondria are the checkpoint of the intrinsic pathway of apoptosis: the release of caspase cofactors, such as cytochrome c (cyt c) and SMAC/Diablo, results in the assembly of the apoptosome and in commitment of the cell to apoptosis. ![]()
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March 2023
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