PDF(Pubmed)
Abstract：
Alterations in the function of K+ channels such as the voltage- and Ca2+-activated K+ channel of large conductance (BKCa) reportedly promote breast cancer (BC) development and progression. Underlying molecular mechanisms remain, however, elusive. Here, we provide electrophysiological evidence for a BKCa splice variant localized to the inner mitochondrial membrane of murine and human BC cells (mitoBKCa). Through a combination of genetic knockdown and knockout along with a cell permeable BKCa channel blocker, we show that mitoBKCa modulates overall cellular and mitochondrial energy production, and mediates the metabolic rewiring referred to as the \'Warburg effect\', thereby promoting BC cell proliferation in the presence and absence of oxygen. Additionally, we detect mitoBKCa and BKCa transcripts in low or high abundance, respectively, in clinical BC specimens. Together, our results emphasize, that targeting mitoBKCa could represent a treatment strategy for selected BC patients in future.
摘要：
据报道，K通道功能的改变，例如大电导的电压和Ca2激活的K通道（BKCa）促进了乳腺癌（BC）的发展和进展。潜在的分子机制仍然存在，然而,难以捉摸。这里,我们提供了位于鼠和人BC细胞（mitoBKCa）线粒体内膜的BKCa剪接变体的电生理学证据。通过基因敲除和敲除以及细胞可渗透的BKCa通道阻断剂的组合，我们显示mitoBKCa调节整体细胞和线粒体能量产生，并介导称为“Warburg效应”的代谢重新布线，从而在存在和不存在氧的情况下促进BC细胞增殖。此外,我们检测出低或高丰度的mitoBKCa和BKCa转录本，分别,在临床BC标本中。一起,我们的结果强调，靶向mitoBKCa可能代表未来选定的BC患者的治疗策略。
