TASK-1 Regulates Apoptosis and Proliferation in a Subset of Non-Small Cell Lung Cancers.
TASK-1 Regulates Apoptosis and Proliferation in a Subset of Non-Small Cell Lung Cancers.
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DOI：
10.1371/journal.pone.0157453
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Hrzenjak A
中科院分区：
文献类型：
--
作者：
Leithner K;Hirschmugl B;Li Y;Tang B;Papp R;Nagaraj C;Stacher E;Stiegler P;Lindenmann J;Olschewski A;Olschewski H;Hrzenjak A
肺癌是世界范围内癌症死亡的主要原因;尽管有治疗，但存活时间很短。双孔结构域K+（K2 P）通道ASK-1（KCNK 3）在肺癌中的作用目前尚不清楚。我们发现，在非小细胞肺癌（NSCLC）细胞系中，TASK-1的表达水平是可变的。在一个高表达的非小细胞肺癌细胞系A549中，测量到一个特征性的pH和缺氧敏感性非失活K+电流，表明存在功能性的ASK-1通道。抑制Task-I导致这些细胞中的显著去极化。通过siRNA敲低ASK-1显著增强了A549细胞的凋亡并降低了增殖，但在弱表达ASK-1的NCI-H358细胞中没有。Na+-偶联的营养物质跨细胞膜的转运在功能上与K+通过K+通道的流出偶联，因此，ASK-1可能潜在地影响Na+-偶联的营养物质转运。与在肺癌与正常肺组织中没有差异表达的ASK-1相反，我们发现Na+偶联营养转运蛋白SLC 5A 3、SLC 5A 6和SLC 38 A1（分别为肌醇、生物素和谷氨酰胺的转运蛋白）在肺腺癌中显著过表达。总之，我们第一次证明了在NSCLC的一个亚组中，ASK-1通道调节细胞凋亡和增殖。
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.