Division of Animal and Human Physiology, Department of Biology, National and Kapodistrian University of Athens, Panepistimiopolis, 15784, Athens, Greece.
Center for Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation, Academy of Athens, Soranou Efesiou 4, 11527, Athens, Greece.
Cell Biol Toxicol. 2016 Oct;32(5):437-49. doi: 10.1007/s10565-016-9345-x. Epub 2016 Jun 25.
Calcium signaling participates in the regulation of numberless cellular functions including cell cycle progression and cellular migration, important processes for cancer expansion. Cancer cell growth, migration, and invasion are typically supported by PI3K/Akt activation, while a hypoxic environment is critical in cancer development. Accordingly, in the present study, we aimed at investigating whether perturbations in calcium homeostasis induce alterations of HIF-1α and activate Akt levels in epithelial A549 and A431 cells. Survival was drastically reduced in the presence of calcium chelator BAPTA-AM and thapsigargin, a SERCA inhibitor inducing store-operated calcium entry, to a lesser extent. Calcium chelation provoked a transient but strong upregulation of HIF-1α protein levels and accumulation in the nucleus, whereas in the presence of thapsigargin, HIF-1α levels were rapidly abolished before reaching and exceeding control levels. Despite cell death, calcium chelation merely inhibited Akt, which was significantly activated in the presence of thapsigargin. Moreover, when store-operated calcium entry was simulated by reintroducing calcium ions in cell suspensions, Akt was rapidly activated in the absence of any growth factor. These data further underscore the growing importance of calcium entry and directly link this elementary event of calcium homeostasis to the Akt pathway, which is commonly deregulated in cancer.
钙信号参与调节无数细胞功能，包括细胞周期进程和细胞迁移，这些都是癌症扩散的重要过程。PI3K/Akt 的激活通常支持癌细胞的生长、迁移和侵袭，而缺氧环境对癌症的发展至关重要。因此，在本研究中，我们旨在研究钙稳态的改变是否会诱导上皮 A549 和 A431 细胞中 HIF-1α 的改变并激活 Akt 水平。在存在钙螯合剂 BAPTA-AM 和 thapsigargin（一种诱导内质网钙库操纵性钙内流的 SERCA 抑制剂）的情况下，细胞存活率显著降低，而在钙螯合剂存在的情况下，HIF-1α 蛋白水平短暂但强烈地上调，并在细胞核中积累，而 thapsigargin 的存在会迅速导致 HIF-1α 水平被消除，然后超过对照水平。尽管发生了细胞死亡，但钙螯合剂仅抑制 Akt，而在 thapsigargin 存在下，Akt 被显著激活。此外，当通过在细胞悬浮液中重新引入钙离子来模拟内质网钙库操纵性钙内流时，Akt 在没有任何生长因子的情况下迅速被激活。这些数据进一步强调了钙内流的重要性，并将钙稳态的这一基本事件直接与 Akt 通路联系起来，而 Akt 通路在癌症中通常失调。
