Leithner Katharina, Hirschmugl Birgit, Li Yingji, Tang Bi, Papp Rita, Nagaraj Chandran, Stacher Elvira, Stiegler Philipp, Lindenmann Jörg, Olschewski Andrea, Olschewski Horst, Hrzenjak Andelko
Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria.
PLoS One. 2016 Jun 13;11(6):e0157453. doi: 10.1371/journal.pone.0157453. eCollection 2016.
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.
肺癌是全球癌症死亡的主要原因；尽管进行了治疗，但生存时间仍很短。目前，双孔域钾离子（K2P）通道TASK-1（KCNK3）在肺癌中的作用尚不清楚。我们发现TASK-1在非小细胞肺癌（NSCLC）细胞系中以不同水平表达。在高表达TASK-1的NSCLC细胞系A549中，检测到一种特征性的对pH和缺氧敏感的非失活钾离子电流，表明存在功能性TASK-1通道。抑制TASK-1会导致这些细胞发生明显的去极化。通过小干扰RNA（siRNA）敲低TASK-1可显著增强A549细胞的凋亡并减少其增殖，但在低表达TASK-1的NCI-H358细胞中则无此作用。跨细胞膜的钠偶联营养物质转运在功能上与通过钾离子通道的钾离子外流相关联，因此TASK-1可能会潜在地影响钠偶联营养物质转运。与在肺癌组织和正常肺组织中无差异表达的TASK-1不同，我们发现钠偶联营养物质转运体SLC5A3、SLC5A6和SLC38A1（分别是肌醇、生物素和谷氨酰胺的转运体）在肺腺癌中显著过表达。总之，我们首次表明TASK-1通道在一部分NSCLC中调节细胞凋亡和增殖。
