Abstract
Previous results link the mitochondrial potassium channel Kv1.3 (mitoKv1.3) to the regulation of apoptosis. By synthesizing new, mitochondria-targeted derivatives (PAPTP and PCARBTP) of PAP-1, a specific membrane-permeant Kv1.3 inhibitor, we have recently provided evidence that both drugs acting on mitoKv1.3 are able to induce apoptosis and reduce tumor growth in vivo without affecting healthy tissues and cells. In the present article, by exploiting these new drugs, we addressed the question whether mitoKv1.3 contributes to the regulation of cell proliferation as well. When used at low concentrations, which do not compromise cell survival, both drugs slightly increased the percentage of cells in S phase while decreased the population at G0/G1 stage of cells from two different pancreatic ductal adenocarcinoma lines. Our data suggest that the observed modulation is related to ROS levels within the cells, opening the way to link mitochondrial ion channel function to downstream, ROS-related signaling events that might be important for cell cycle progression.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is considered a silent killer
The decrease of MTS values was due to apoptosis, as 10 μM PAPTP or PCARBTP caused a drastic increase in programmed cell death as assessed using Annexin V staining (Figure 2), while clofazimine even at 20 μM concentration induced only less than 30% cell death
Modulation of the membrane potential is required for both G1/S phase and G2/M phase transitions: during G1/S the cell membrane becomes hyperpolarized relative to the resting potential as voltage-gated Kv potassium channels mediate the efflux of positively charged K+ ions from the cells to the extracellular milieu, e.g., Ref. [29, 30]; depolarization of the Plasma membrane (PM) seems to be essential for the G2/M transition
Summary
Pancreatic ductal adenocarcinoma (PDAC) is considered a silent killer. A large number of new cases arise every year, but the lifespan of the patients is always very short, with a survival percentage around 25% 5 years after diagnosis [1]. PDAC treatment is limited prevalently to the use of fluorouracil or gemcitabine either alone or in combination and to surgery following diagnosis [2]. An important role has been assigned to ion channels: these proteins have been related to several hallmarks of cancer, ranging from resistance to cell death, to modifying and controlling cell cycle progression, as well as to favor tumor progression and metastasis formation [3,4,5]. Potassium (K+) channels are present in basically every organism, ranging from virus to mammals and permit K+ transport across biological membranes. They are formed by tetramers of four α subunits and by regulatory β and γ subunits. The selectivity filter is almost universal and is formed by a five residue-long signature sequence (TVGYG) within the pore loop of each subunit, as it has been demonstrated both by site-directed mutagenesis combined with electrophysiology
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