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Inhibition of casein kinase 1-epsilon induces cancer-cell-selective, PERIOD2-dependent growth arrest.

Yang WS, Stockwell BR - Genome Biol. (2008)

Bottom Line: We employed a two-step screening strategy using human sarcoma cell lines and human fibroblast-derived isogenic cell lines, and found that short hairpin RNAs targeting CSNK1E, a clock gene that regulates circadian rhythms, can induce selective growth inhibition in engineered tumor cells.Treatment with IC261, a kinase domain inhibitor of casein kinase 1-epsilon (CK1epsilon), a protein product of CSNK1E, showed a similar degree of cancer-cell-selective growth inhibition.These data support the hypothesis that circadian clock genes can control the cell cycle and cell survival signaling, and emphasize a central role of CK1epsilon and PERIOD2 in linking these systems.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biological Sciences, Columbia University, Fairchild Center, Amsterdam Avenue, New York, NY 10027, USA.

ABSTRACT

Background: Kinases are under extensive investigation as targets for drug development. Discovering novel kinases whose inhibition induces cancer-cell-selective lethality would be of value. Recent advances in RNA interference have enabled the realization of this goal.

Results: We screened 5,760 short hairpin RNA clones targeting the human kinome to detect human kinases on which cancer cells are more dependent than normal cells. We employed a two-step screening strategy using human sarcoma cell lines and human fibroblast-derived isogenic cell lines, and found that short hairpin RNAs targeting CSNK1E, a clock gene that regulates circadian rhythms, can induce selective growth inhibition in engineered tumor cells. Analysis of gene-expression data revealed that CSNK1E is overexpressed in several cancer tissue samples examined compared to non-tumorigenic normal tissue, suggesting a positive role of CSNK1E in neogenesis or maintenance. Treatment with IC261, a kinase domain inhibitor of casein kinase 1-epsilon (CK1epsilon), a protein product of CSNK1E, showed a similar degree of cancer-cell-selective growth inhibition. In a search for substrates of CK1epsilon that mediate IC261-induced growth inhibition, we discovered that knocking down PER2, another clock gene involved in circadian rhythm control, rescues IC261-induced growth inhibition.

Conclusion: We identified CK1epsilon as a potential target for developing anticancer reagents with a high therapeutic index. These data support the hypothesis that circadian clock genes can control the cell cycle and cell survival signaling, and emphasize a central role of CK1epsilon and PERIOD2 in linking these systems.

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Gene expression studies comparing normal and cancer tissues were analyzed for CSNK1E using Oncomine [21]. CSNK1E was found to be over-expressed in cancer samples over normal samples regardless of tissue origin. The graph shows representative results of CSNK1E gene expression analysis from six human tissues. The number of samples in each study is provided in parentheses. The y-axis units are based on z-score normalization and the P-value of each set is shown at the bottom of the graph. The upper and lower bands of the box represent the 75th and 25th percentiles, respectively; the upper and lower error bars represent the 90th and 10th percentiles, respectively. The table shows normalized expression levels of CSNK1E in normal and cancer samples from ten human tissues.
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Figure 3: Gene expression studies comparing normal and cancer tissues were analyzed for CSNK1E using Oncomine [21]. CSNK1E was found to be over-expressed in cancer samples over normal samples regardless of tissue origin. The graph shows representative results of CSNK1E gene expression analysis from six human tissues. The number of samples in each study is provided in parentheses. The y-axis units are based on z-score normalization and the P-value of each set is shown at the bottom of the graph. The upper and lower bands of the box represent the 75th and 25th percentiles, respectively; the upper and lower error bars represent the 90th and 10th percentiles, respectively. The table shows normalized expression levels of CSNK1E in normal and cancer samples from ten human tissues.

Mentions: The CSNK1E gene encodes the CK1ε protein, whose main function is to regulate the circadian rhythm by phosphorylating other clock gene products [18]. The role of CK1ε in cancer has been speculated upon, because CK1ε was shown to phosphorylate key proteins in cancer signaling pathways, such as p53 [19] and β-catenin [20]. However, the significance of these phosphorylation events in carcinogenesis is not known, and the possibility of using CK1ε as a pharmacological target for cancer treatment has not been considered. Therefore, we analyzed the expression level of CSNK1E in human tumor samples to obtain support for its involvement in human cancer. Some genes that are specifically required for tumor maintenance are overexpressed in cancer cells over normal cells. We analyzed the gene-expression database Oncomine for differential expression patterns in normal versus tumor in different tissue types [21]. The Oncomine database contained microarray expression data for CSNK1E from ten different tissues, including brain, head and neck, renal, bladder, leukemia, lung, melanoma, prostate, salivary gland, and seminoma. Interestingly, all tumor tissues in the database showed upregulated CSNK1E expression compared to normal tissues, suggesting a positive role of CK1ε in cancer maintenance or neogenesis (Figure 3).


Inhibition of casein kinase 1-epsilon induces cancer-cell-selective, PERIOD2-dependent growth arrest.

Yang WS, Stockwell BR - Genome Biol. (2008)

Gene expression studies comparing normal and cancer tissues were analyzed for CSNK1E using Oncomine [21]. CSNK1E was found to be over-expressed in cancer samples over normal samples regardless of tissue origin. The graph shows representative results of CSNK1E gene expression analysis from six human tissues. The number of samples in each study is provided in parentheses. The y-axis units are based on z-score normalization and the P-value of each set is shown at the bottom of the graph. The upper and lower bands of the box represent the 75th and 25th percentiles, respectively; the upper and lower error bars represent the 90th and 10th percentiles, respectively. The table shows normalized expression levels of CSNK1E in normal and cancer samples from ten human tissues.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2481424&req=5

Figure 3: Gene expression studies comparing normal and cancer tissues were analyzed for CSNK1E using Oncomine [21]. CSNK1E was found to be over-expressed in cancer samples over normal samples regardless of tissue origin. The graph shows representative results of CSNK1E gene expression analysis from six human tissues. The number of samples in each study is provided in parentheses. The y-axis units are based on z-score normalization and the P-value of each set is shown at the bottom of the graph. The upper and lower bands of the box represent the 75th and 25th percentiles, respectively; the upper and lower error bars represent the 90th and 10th percentiles, respectively. The table shows normalized expression levels of CSNK1E in normal and cancer samples from ten human tissues.
Mentions: The CSNK1E gene encodes the CK1ε protein, whose main function is to regulate the circadian rhythm by phosphorylating other clock gene products [18]. The role of CK1ε in cancer has been speculated upon, because CK1ε was shown to phosphorylate key proteins in cancer signaling pathways, such as p53 [19] and β-catenin [20]. However, the significance of these phosphorylation events in carcinogenesis is not known, and the possibility of using CK1ε as a pharmacological target for cancer treatment has not been considered. Therefore, we analyzed the expression level of CSNK1E in human tumor samples to obtain support for its involvement in human cancer. Some genes that are specifically required for tumor maintenance are overexpressed in cancer cells over normal cells. We analyzed the gene-expression database Oncomine for differential expression patterns in normal versus tumor in different tissue types [21]. The Oncomine database contained microarray expression data for CSNK1E from ten different tissues, including brain, head and neck, renal, bladder, leukemia, lung, melanoma, prostate, salivary gland, and seminoma. Interestingly, all tumor tissues in the database showed upregulated CSNK1E expression compared to normal tissues, suggesting a positive role of CK1ε in cancer maintenance or neogenesis (Figure 3).

Bottom Line: We employed a two-step screening strategy using human sarcoma cell lines and human fibroblast-derived isogenic cell lines, and found that short hairpin RNAs targeting CSNK1E, a clock gene that regulates circadian rhythms, can induce selective growth inhibition in engineered tumor cells.Treatment with IC261, a kinase domain inhibitor of casein kinase 1-epsilon (CK1epsilon), a protein product of CSNK1E, showed a similar degree of cancer-cell-selective growth inhibition.These data support the hypothesis that circadian clock genes can control the cell cycle and cell survival signaling, and emphasize a central role of CK1epsilon and PERIOD2 in linking these systems.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biological Sciences, Columbia University, Fairchild Center, Amsterdam Avenue, New York, NY 10027, USA.

ABSTRACT

Background: Kinases are under extensive investigation as targets for drug development. Discovering novel kinases whose inhibition induces cancer-cell-selective lethality would be of value. Recent advances in RNA interference have enabled the realization of this goal.

Results: We screened 5,760 short hairpin RNA clones targeting the human kinome to detect human kinases on which cancer cells are more dependent than normal cells. We employed a two-step screening strategy using human sarcoma cell lines and human fibroblast-derived isogenic cell lines, and found that short hairpin RNAs targeting CSNK1E, a clock gene that regulates circadian rhythms, can induce selective growth inhibition in engineered tumor cells. Analysis of gene-expression data revealed that CSNK1E is overexpressed in several cancer tissue samples examined compared to non-tumorigenic normal tissue, suggesting a positive role of CSNK1E in neogenesis or maintenance. Treatment with IC261, a kinase domain inhibitor of casein kinase 1-epsilon (CK1epsilon), a protein product of CSNK1E, showed a similar degree of cancer-cell-selective growth inhibition. In a search for substrates of CK1epsilon that mediate IC261-induced growth inhibition, we discovered that knocking down PER2, another clock gene involved in circadian rhythm control, rescues IC261-induced growth inhibition.

Conclusion: We identified CK1epsilon as a potential target for developing anticancer reagents with a high therapeutic index. These data support the hypothesis that circadian clock genes can control the cell cycle and cell survival signaling, and emphasize a central role of CK1epsilon and PERIOD2 in linking these systems.

Show MeSH
Related in: MedlinePlus