Research Service, Minneapolis VA Health Care System, Minneapolis, MN, 55417, USA.
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, 55455, USA.
Mol Cell Biochem. 2020 Jul;470(1-2):131-143. doi: 10.1007/s11010-020-03752-4. Epub 2020 May 20.
Protein kinase CK2 plays multiple roles in cell function in normal and disease states. CK2 is elevated in numerous types of cancer cells, and CK2 suppression of apoptosis represents a key link to the cancer cell phenotype. CK2 regulation of cell survival and death involves diverse processes, and our previous work suggested that mitochondrial machinery is a key locus of this function. One of the earliest responses of prostate cells to inhibition of CK2 is a change in mitochondrial membrane potential, possibly associated with Ca signaling. Thus, in the present work, we investigated early impact of CK2 on intracellular Ca dynamics. Three prostate cancer (PCa) cell lines, PC3-LN4, C4-2B, and 22Rv1, were studied. PCa cells were treated with the CK2 small molecule inhibitors 4,5,6,7-tetrabrombenzotriazole and CX-4945 followed by analysis of Ca levels in various cellular compartments over time. The results showed dose-dependent loss in cytosolic Ca levels starting within 2 min and reaching maximal loss within 5-10 min. There was a concomitant increase in Ca in the endoplasmic reticulum (ER) and mitochondrial compartments. The results suggest that inhibition of CK2 activity results in a rapid movement of Ca out of the cytosol and into the ER and mitochondria, which may be among the earliest contributory factors for induction of apoptosis in cells subjected to inhibition of CK2. In cells with death-inducing levels of CK2 inhibition, total cellular Ca levels dropped at 2 h post-treatment. These novel observations represent a potential mechanism underlying regulation of cell survival and death by CK2 activity.
蛋白激酶 CK2 在正常和疾病状态下的细胞功能中发挥多种作用。CK2 在许多类型的癌细胞中升高，CK2 对细胞凋亡的抑制代表了癌细胞表型的关键环节。CK2 对细胞存活和死亡的调节涉及多种过程，我们之前的工作表明，线粒体机制是该功能的关键位置。前列腺细胞对 CK2 抑制的最早反应之一是线粒体膜电位的变化，可能与 Ca 信号有关。因此，在本工作中，我们研究了 CK2 对细胞内 Ca 动力学的早期影响。研究了三种前列腺癌细胞系（PCa），PC3-LN4、C4-2B 和 22Rv1。用 CK2 小分子抑制剂 4,5,6,7-四溴苯并三唑和 CX-4945 处理 PCa 细胞，然后随时间分析细胞内各腔室的 Ca 水平。结果表明，从 2 分钟开始，细胞溶质 Ca 水平呈剂量依赖性下降，在 5-10 分钟内达到最大下降。内质网（ER）和线粒体腔室中的 Ca 含量同时增加。结果表明，CK2 活性的抑制导致 Ca 迅速从细胞溶质中移出并进入 ER 和线粒体，这可能是 CK2 抑制后诱导细胞凋亡的最早促成因素之一。在 CK2 抑制诱导死亡的细胞中，总细胞 Ca 水平在处理后 2 小时下降。这些新的观察结果代表了 CK2 活性调节细胞存活和死亡的潜在机制。
