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


CONCLUSIONS
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.
Department of Biological Sciences, Columbia University, Fairchild Center, Amsterdam Avenue, New York, NY 10027, USA.
Wan Seok
WS
Yang
Brent R
BR
Stockwell
D048149:Casein Kinase 1 epsilon / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D002470:Cell Survival; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy; D009687:Nuclear Proteins / Q000378:metabolism*; D056950:Period Circadian Proteins; D010696:Phloroglucinol / Q000031:analogs & derivatives* / Q000494:pharmacology; D034622:RNA Interference; D014157:Transcription Factors / Q000378:metabolism*
C411652:IC 261; D007211:Indoles; D009687:Nuclear Proteins; C421902:PER2 protein, human; D056950:Period Circadian Proteins; D014157:Transcription Factors; D010696:Phloroglucinol; D048149:Casein Kinase 1 epsilon