Department of Molecular and Cellular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabedori Mizuhoku, Nagoya, 467-8603, Japan.
Department of Molecular and Cellular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabedori Mizuhoku, Nagoya, 467-8603, Japan.
Biochem Biophys Res Commun. 2020 May 14;525(4):1032-1037. doi: 10.1016/j.bbrc.2020.02.176. Epub 2020 Mar 13.
Pancreatic neuroendocrine tumors (pNETs) occur due to the abnormal growth of pancreatic islet cells and predominantly develop in the duodenal-pancreatic region. Somatostatinoma is one of the pNETs associated with tumors of pancreatic δ cells, which produce and secrete somatostatin. Limited information is currently available on the pathogenic mechanisms of somatostatinoma. The large-conductance Ca-activated K (BK) channel is expressed in several types of cancer cells and regulates cell proliferation, migration, invasion, and metastasis. In the present study, the functional expression of the BK channel was examined in a human somatostatinoma QGP-1 cell line. In QGP-1 cells, outward currents were elicited by membrane depolarization at pCa 6.5 (300 nM) in the pipette solution and inhibited by the specific BK channel blocker, paxilline. Paxilline-sensitive currents were detected, even at pCa 8.0 (10 nM) in the pipette solution, in QGP-1 cells. In addition to the α and β2-4 subunits of the BK channel, the novel regulatory γ1 subunit (BKγ1) was co-localized with the α subunit in QGP-1 cells. Paxilline-sensitive currents at pCa 8.0 in the pipette solution were reduced by the siRNA knockdown of BKγ1. Store-operated Ca entry was smaller in BKγ1 siRNA-treated QGP-1 cells. The proliferation of QGP-1 cells was attenuated by paxilline or the siRNA knockdown of BKγ1. These results strongly suggest that BKγ1 facilitates the proliferation of human somatostatinoma cells. Therefore, BKγ1 may be a novel therapeutic target for somatostatinoma.
胰腺神经内分泌肿瘤（pNETs）是由于胰岛细胞的异常生长引起的，主要发生在十二指肠-胰腺区域。生长抑素瘤是与胰腺 δ 细胞肿瘤相关的 pNETs 之一，其产生和分泌生长抑素。目前关于生长抑素瘤的发病机制的信息有限。大电导钙激活钾（BK）通道在几种类型的癌细胞中表达，并调节细胞增殖、迁移、侵袭和转移。在本研究中，研究了 BK 通道在人源生长抑素瘤 QGP-1 细胞系中的功能表达。在 QGP-1 细胞中，在膜去极化时，在外向电流在 pipette 溶液中的 pCa 6.5（300 nM）下被激发，并被特异性 BK 通道阻滞剂 paxilline 抑制。在 QGP-1 细胞中，即使在 pipette 溶液中的 pCa 8.0（10 nM）下，也可以检测到 paxilline 敏感的电流。除了 BK 通道的 α 和 β2-4 亚基外，新型调节 γ1 亚基（BKγ1）与 α 亚基在 QGP-1 细胞中共定位。在 pipette 溶液中的 pCa 8.0 时，paxilline 敏感的电流在 BKγ1 的 siRNA 敲低后减少。BKγ1 siRNA 处理的 QGP-1 细胞中的钙库操纵性钙内流减少。QGP-1 细胞的增殖在 paxilline 或 BKγ1 的 siRNA 敲低后受到抑制。这些结果强烈表明，BKγ1 促进了人源生长抑素瘤细胞的增殖。因此，BKγ1 可能是生长抑素瘤的一个新的治疗靶点。
