Therapeutic CK2 inhibition attenuates diverse prosurvival signaling cascades and decreases cell viability in human breast cancer cells.

Breast cancer is the most common malignancy in women worldwide and remains a major cause of mortality, thus necessitating further therapeutic advancements. In breast cancer, numerous cell signaling pathways are aberrantly activated to produce the myriad phenotypes associated with malignancy; such pathways include the PI3K/Akt/mTOR, NF-κB and JAK/STAT cascades. These pathways are highly interconnected, but one prominent lateral enhancer of each is the remarkably promiscuous kinase CK2. CK2 expression has been shown to be elevated in cancer, thus implicating it in tumorigenesis through its effects on oncogenic signaling cascades. In this study, we identify aberrant expression of CK2 subunits in human breast samples from The Cancer Genome Atlas dataset. Additionally, two specific small molecule inhibitors of CK2, CX-4945 and TBB, were used to examine the role of CK2 in two human breast cancer cell lines, MDA-MB-231 and MCF-7 cells. We show that CK2 inhibition attenuates constitutive PI3K/Akt/mTOR, NF-κB and STAT3 activation and inducible NF-κB and JAK/STAT activation and downstream transcriptional activity. CX-4945 treatment caused a range of phenotypic changes in these cell lines, including decreased viability, cell cycle arrest, apoptosis and loss of migratory capacity. Overall, these results demonstrate the tremendous potential of CK2 as a clinical target in breast cancer.

乳腺癌是全球女性中最常见的恶性肿瘤，并且仍然是导致死亡的主要原因，因此需要进一步的治疗进展。在乳腺癌中，许多细胞信号通路异常激活，产生与恶性肿瘤相关的无数表型；这些通路包括PI3K/Akt/mTOR、NF - κB和JAK/STAT级联反应。这些通路高度相互关联，但其中一个显著的横向增强因子是极其混杂的激酶CK2。已表明CK2的表达在癌症中升高，因此通过其对致癌信号级联反应的影响而与肿瘤发生有关。在这项研究中，我们从癌症基因组图谱数据集中确定了人乳腺样本中CK2亚基的异常表达。此外，使用了两种特异性的CK2小分子抑制剂CX - 4945和TBB，来研究CK2在两种人乳腺癌细胞系MDA - MB - 231和MCF - 7细胞中的作用。我们表明CK2抑制减弱了组成性的PI3K/Akt/mTOR、NF - κB和STAT3激活以及诱导性的NF - κB和JAK/STAT激活和下游转录活性。CX - 4945处理导致这些细胞系出现一系列表型变化，包括活力降低、细胞周期停滞、细胞凋亡和迁移能力丧失。总体而言，这些结果证明了CK2作为乳腺癌临床靶点的巨大潜力。