Effects of altered expression and activity levels of CK1[delta] and on tumor growth and survival of colorectal cancer patients

Colorectal cancer (CRC) is the fourth leading cause of cancer related death worldwide due to high apoptotic resistance and metastatic potential. Because mutations as well as deregulation of CK1 isoforms contribute to tumor development and tumor progression, CK1 has become an interesting drug target. In this study we show that CK1 isoforms are differently expressed in colon tumor cell lines and that growth of these cell lines can be inhibited by CK1-specific inhibitors. Furthermore, expression of CK1[delta] and is changed in colorectal tumors compared to normal bowel epithelium, and high CK1 expression levels significantly correlate with prolonged patients' survival. In addition to changes in CK1[delta] and expression, mutations within exon 3 of CK1[delta] were detected in colorectal tumors. These mutations influence ATP binding resulting in changes in kinetic parameters of CK1[delta]. Overexpression of these mutants in HT29 cells alters their ability to grow anchorage independently. Consistent with these results, these CK1[delta] mutants lead to differences in proliferation rate and tumor size in xenografts due to changes in gene expression, especially in genes involved in regulation of cell proliferation, cell cycle, and apoptosis. In summary, our results provide evidence that changes in the expression levels of CK1 isoforms in colorectal tumors correlate with patients' survival. Furthermore, CK1 mutants affect growth and proliferation of tumor cells and induce tumor growth in xenografts, leading to the assumption that CK1 isoforms provide interesting targets for the development of novel effective therapeutic concepts to treat colorectal cancer. What's new? Mutations and alterations in the expression and activity of CK1 isoforms--which play important roles in many cellular processes--are known to contribute to tumorigenesis and tumor progression. The authors show that expression of CK1 correlates with the survival of colorectal cancer patients. Furthermore, they identify CK1[delta] mutations leading to altered kinetic parameters in vitro and, when introduced into a carcinoma cell line, altered tumor growth in vivo. Since the mutant with high oncogenic potential also displays greater sensitivity to CK1-specific inhibitors, the findings underline the potential use of CK1-specific inhibitors in the treatment of colorectal cancer and personalized medicine.