PDF(Pubmed)
Abstract：
No data are currently available on the functional role of small conductance Ca2+-activated K+ channels (SKCa) in ovarian cancer. Here, we characterized the role of SK2 (KCa2.2) in ovarian cancer cell migration and chemosensitivity. Using the selective non-cell-permeant SK2 inhibitor Lei-Dab7, we identified functional SK2 channels at the plasma membrane, regulating store-operated Ca2+ entry (SOCE) in both cell lines tested (COV504 and OVCAR3). Silencing KCNN2 with short interfering RNA (siRNA), or blocking SK2 activity with Lei-Dab7, decreased cell migration. The more robust effect of KCNN2 knockdown compared to Lei-Dab7 treatment suggested the involvement of functional intracellular SK2 channels in both cell lines. In cells treated with lysophosphatidic acid (LPA), an ovarian cancer biomarker of progression, SK2 channels are a key player of LPA pro-migratory activity but their role in SOCE is abolished. Concerning chemotherapy, SK2 inhibition increased chemoresistance to Taxol® and low KCNN2 mRNA expression was associated with the worst prognosis for progression-free survival in patients with serous ovarian cancer. The dual roles of SK2 mean that SK2 activators could be used as an adjuvant chemotherapy to potentiate treatment efficacy and SK2 inhibitors could be administrated as monotherapy to limit cancer cell dissemination.
摘要：
目前尚无有关小电导Ca2激活的K通道（SKCa）在卵巢癌中的功能作用的数据。这里,我们研究了SK2(KCa2.2)在卵巢癌细胞迁移和化疗敏感性中的作用.使用选择性非细胞渗透性SK2抑制剂Lei-Dab7，我们鉴定了质膜上的功能性SK2通道，在测试的两种细胞系(COV504和OVCAR3)中调节存储操作的Ca2+进入(SOCE)。用短干扰RNA（siRNA）沉默KCNN2，或者用Lei-Dab7阻断SK2活性，降低细胞迁移。与Lei-Dab7处理相比,KCNN2敲低的更强效果表明功能性细胞内SK2通道参与两种细胞系。在用溶血磷脂酸（LPA）处理的细胞中，卵巢癌进展的生物标志物，SK2通道是LPA促进迁徙活动的关键参与者，但其在SOCE中的作用已被废除。关于化疗，SK2抑制增加对Taxol®的化学抗性和低KCNN2mRNA表达与浆液性卵巢癌患者无进展生存期的最差预后相关。SK2的双重作用意味着SK2激活剂可以用作辅助化疗以增强治疗功效,并且SK2抑制剂可以作为单一疗法施用以限制癌细胞播散。
