Thoracic Oncology Laboratory, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California, United States of America.
PLoS One. 2012;7(6):e38996. doi: 10.1371/journal.pone.0038996. Epub 2012 Jun 29.
Protein kinase CK2 is frequently elevated in a variety of human cancers. The Hedgehog (Hh) signaling pathway has been implicated in stem cell maintenance, and its aberrant activation has been indicated in several types of cancer, including lung cancer. In this study, we show that CK2 is positively involved in Hh/Gli signaling in lung cancer cell lines A549 and H1299. First, we found a correlation between CK2α and Gli1 mRNA levels in 100 primary lung cancer tissues. Down-regulation of Gli1 expression and transcriptional activity were demonstrated after the silencing of CK2α in lung cancer cells. In addition, CK2α siRNA down-regulated the expression of Hh target genes. Furthermore, two small-molecule CK2α inhibitors led to a dose-dependent inhibition of Gli1 expression and transcriptional activity in lung cancer cells. Reversely, forced over-expression of CK2α resulted in an increase both in Gli1 expression and transcriptional activity in A549 cells. Finally, the inhibition of Hh/Gli by CK2α siRNA led to a reduction of a cancer stem cell-like side population that shows higher ABCG2 expression level. Thus, we report that the inhibition of CK2α down-regulates Hh/Gli signaling and subsequently reduces stem-like side population in human lung cancer cells.
蛋白激酶 CK2 在多种人类癌症中经常升高。Hedgehog（Hh）信号通路与干细胞维持有关，其异常激活已在包括肺癌在内的多种类型的癌症中得到证实。在这项研究中，我们表明 CK2 积极参与肺癌细胞系 A549 和 H1299 中的 Hh/Gli 信号转导。首先，我们在 100 份原发性肺癌组织中发现 CK2α 和 Gli1 mRNA 水平之间存在相关性。在肺癌细胞中沉默 CK2α 后，Gli1 表达和转录活性均降低。此外，CK2α siRNA 下调了 Hh 靶基因的表达。此外，两种小分子 CK2α 抑制剂可在肺癌细胞中剂量依赖性地抑制 Gli1 的表达和转录活性。相反，CK2α 的强制过表达导致 A549 细胞中 Gli1 表达和转录活性的增加。最后，CK2α siRNA 对 Hh/Gli 的抑制导致具有更高 ABCG2 表达水平的癌症干细胞样侧群减少。因此，我们报告 CK2α 的抑制下调了 Hh/Gli 信号转导，随后减少了人肺癌细胞中的干细胞样侧群。
