Abstract
Lung cancer is the leading cause of cancer deaths worldwide; survival times are poor despite therapy. The role of the two-pore domain K+ (K2P) channel TASK-1 (KCNK3) in lung cancer is at present unknown. We found that TASK-1 is expressed in non-small cell lung cancer (NSCLC) cell lines at variable levels. In a highly TASK-1 expressing NSCLC cell line, A549, a characteristic pH- and hypoxia-sensitive non-inactivating K+ current was measured, indicating the presence of functional TASK-1 channels. Inhibition of TASK-1 led to significant depolarization in these cells. Knockdown of TASK-1 by siRNA significantly enhanced apoptosis and reduced proliferation in A549 cells, but not in weakly TASK-1 expressing NCI-H358 cells. Na+-coupled nutrient transport across the cell membrane is functionally coupled to the efflux of K+ via K+ channels, thus TASK-1 may potentially influence Na+-coupled nutrient transport. In contrast to TASK-1, which was not differentially expressed in lung cancer vs. normal lung tissue, we found the Na+-coupled nutrient transporters, SLC5A3, SLC5A6, and SLC38A1, transporters for myo-inositol, biotin and glutamine, respectively, to be significantly overexpressed in lung adenocarcinomas. In summary, we show for the first time that the TASK-1 channel regulates apoptosis and proliferation in a subset of NSCLC.
Highlights
Lung cancer accounts for the largest number of cancer deaths worldwide [1]
TASK-1 is expressed in a subset of non-small cell lung cancers (NSCLC) cell lines and NSCLC tissues
TASK-1 protein was consistently detectable by immunoblotting in four of the eight cell lines (A549, H358, H460, and MOR), the strongest expression being found in A549, H460, and MOR cells (Fig 1A)
Summary
Lung cancer accounts for the largest number of cancer deaths worldwide [1]. Approximately 85% of lung cancers are non-small cell lung cancers (NSCLC) and 15% are small-cell lung cancers. While many K+ channels open upon a specific trigger, e.g. changes in the membrane potential, K2P channels are constitutively active. K2P channels are grouped into six subfamilies based on their structural and functional properties. Besides different functions in neurons, TASK-1 has been shown to be functionally expressed in the heart, and to set the resting membrane potential and regulate the tone in smooth muscle cells of the pulmonary arteries, intestine, and bladder [5,7]. Since the control of the membrane potential is important in non-excitable cells, e.g. for the control of voltage-dependent calcium entry, and for Na+-driven solute transport, we assessed whether TASK-1 is functionally expressed in lung cancer cells and human lung cancers
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