Article

Inhibition of CK2α Down-Regulates Hedgehog/Gli Signaling Leading to a Reduction of a Stem-Like Side Population in Human Lung Cancer Cells

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 (Impact Factor: 3.23). 06/2012; 7(6):e38996. DOI: 10.1371/journal.pone.0038996
Source: PubMed

ABSTRACT

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.

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Available from: Jian-Hua Mao, Aug 28, 2014
    • "Hedgehog inhibition in combination with cisplatin increased the cytotoxic effects of cisplatin when compared to cisplatinonly treatment[78]. Small molecule inhibition or gene silencing of CK2α resulted in the down-regulation of the Hedgehog pathway and subsequently induced a reduction of the side population percent- age[108]. Cigarette smoking at diagnosis or during lung cancer treatment is associated with poor prognosis and cigarette smoke has now been shown to promote drug resistance via the expansion of the CSC side population[109]. "
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    • "Prior studies suggest that CK2 may modulate the CSC phenotype through a variety of transcriptional mechanisms. A recent study demonstrates that CK2α is associated with Hedgehog (Hh)-Gli1 and Notch1 pathway transcription factors in lung cancers, where knockdown of CK2α reduced Hh/Gli1 and Notch1 signaling and the stem-like side population [28] [29]. Knockout of the regulatory CK2β subunit in mice inhibited transcription factor Olig2, embryonic neural stem cell proliferation, and oligodendrocyte development [30]. "
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    • "Zhang et al. (2012) expanded on Jia et al's discovery and determined that CK2 can regulate the stem-like side population in human lung cancer cells. Zhang et al. discovered that inhibition of CK2α using small molecule inhibitors or siRNAs reduced expression of Gli1 mRNA and protein, and also decreased Gli1 transcriptional activity (Zhang et al., 2012). In addition, decreasing CK2α expression altered ABCG2 expression which consistently led to a reduction in the cancer stem cell-like side population in the lung cancer cells. "
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