Role for acid-sensitive two-pore domain (K_2P) potassium channels in cancer

Abstract

K_2P channels are of broad interest to pathophysiology, including cancer biology, because they are active at all membrane potentials and, thereby, can influence cellular functions including the activity of other ion channels. To date, expression changes in four K_2P channels have been implicated in cancer and found to impact on cancer hallmark functions. However, no study has assessed the expression of all 15 K_2P channels in cancer or what functional roles K_2P multiple channels have in cancer cells. Therefore, the aim of this thesis was to investigate if acid-sensitive K_2P (TASK; K_2P3.1, K_2P9.1, and K_2P15.1) channel expression provides a functional advantage to human cancer cells. This research had two main lines of investigation: (i) to determine the K_2P channel mRNA and protein expression in a range of cancer tissues and cell lines, in order to establish clinically relevant model cancer cell lines that express K_2P channels, and (ii) to assess if TASK channel inhibition (using published inhibitors) has an impact on cell proliferation, apoptosis, or migration in cancer cell lines. Bioinformatic analysis showed that K_2P channel mRNA was over- or underexpressed in a range of cancers, with several channels showing significant alterations. When the channel expression profile in cancer cell lines was studied, mRNA and protein expression data identified A549 (lung), HCT116 (colorectal), and 786-0 (renal) cells as model systems to study the role of TASK channels in cancer. Next, the role of TASK channels in cancer cell proliferation, apoptosis, and migration was examined. Colorectal cancer cell proliferation was significantly reduced following methanandamide or ruthenium red treatment, consistent with K_2P9.1 channel inhibition, suggesting that K_2P9.1 protein expression in colorectal cancer cell lines has a proliferative benefit. In contrast, TASK channel inhibition did not alter cellular functions in the other cell lines examined. Finally, the effect of conditions experienced within the cancer microenvironment was investigated. N-linked glycosylation was critical for K_2P3.1 channel surface expression, but not K_2P9.1. Incubation in either chronic hypoxia or low glucose failed to alter the cancer cell functions studied. Overall this study had two main findings: (i) K_2P channel mRNA is both overexpressed and underexpressed in cancer, and (ii) that TASK channel inhibition had no impact on cellular functions in most of the cell lines studied. The combination of the functional data presented in this thesis, and published data which have linked K_2P9.1 channel activity to three cancer cell functions indicated that TASK channels may have a cell-specific role which could depend on the cancer type. This suggested that future studies are needed to determine what role the expression of multiple K_2P channels and other ion channels can have in cancer. In addition, to expanding on the findings from this thesis by determining if TASK channel activity can be detected in the cancer cell lines examined here, and using targeted TASK channel modulation to confirm the proliferative role of K_2P9.1 channels in colorectal cancer cells.

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