Intracellular ion channels and cancer

Abstract

Several types of channels play a role in the maintenance of ion homeostasis in subcellular organelles including endoplasmatic reticulum, nucleus, lysosome, endosome, and mitochondria. 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 (Ca2+-dependent BKCa and IKCa, ATP-dependent KATP, Kv1.3, two-pore TWIK-related Acid-Sensitive K+ channel-3 (TASK-3)), Ca2+ uniporter MCU, Mg2+-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 (IP3) receptor, the ER-located Ca2+ depletion sensor STIM1 (stromal interaction molecule 1), a component of the store-operated Ca2+ 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 proteomic 2D-DIGE approach reveals the protein voltage-dependent anion channel 2 as a potential therapeutic target in epithelial thyroid tumours

“…Molecular and Cellular Endocrinology j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / m c e interactions with enzymes able to favour glycolysis (Grills et al, 2011;Leanza et al, 2013;Maldonado et al, 2013). Several authors propose that these proteins have the capacity to act as a facultative regulator or effector of mitochondrial membrane permeabilization (MMP), depending on the initial cytotoxic event (Fiek et al, 1982;Linden and Karlsson, 1996;Schein et al, 1976;Shimizu et al, 1999;Shinohara et al, 2000).…”

Biophysical Characterization and Expression Analysis of Kv1.3 Potassium Channel in Primary Human Leukemic B Cells

“…In addition, a correlation was found between K + channel expression and sensitivity of various cancer cells to apoptotic stimuli [6]. Beside plasma membrane-located channels and transporters, intracellular ion channels have been identified as promising oncological targets as well [7,8].…”

Cryo-EM Structures of the Magnesium Channel CorA Reveal Symmetry Break upon Gating

“…In prokaryotes, the ~200 kDa Mg 2+ -dependent channel CorA is the key pathway for electrophoretic Mg 2+ uptake (Dalmas et al, 2014b; Hmiel et al, 1986; Maguire, 2006). CorA can functionally complement the eukaryotic mitochondrial Mrs2 channel (Kolisek et al, 2003), which is essential for normal mitochondrial activity (Weghuber et al, 2006), and whose abnormal expression has been associated with diseases ranging from cancer to demyelination of neuronal tissue (Kuramoto et al, 2011; Leanza et al, 2013). Recent experimental evidence suggests that Mg 2+ homeostasis through CorA takes place via a negative feedback loop, where Mg 2+ binding at the inter-subunit interfaces leads to channel closure, whereas low Mg 2+ concentrations tend to promote the transition to the open, conductive state (Dalmas et al, 2014b; Pfoh et al, 2012).…”