Effects of altered expression and activity levels of CK1δ and ɛ on tumor growth and survival of colorectal cancer patients

Abstract

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 CK1d and E is changed in colorectal tumors compared to normal bowel epithelium, and high CK1E expression levels significantly correlate with prolonged patients' survival. In addition to changes in CK1d and E expression, mutations within exon 3 of CK1d were detected in colorectal tumors. These mutations influence ATP binding resulting in changes in kinetic parameters of CK1d. Overexpression of these mutants in HT29 cells alters their ability to grow anchorage independently. Consistent with these results, these CK1d 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.Colorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer related death in both men and women worldwide. 1,2 Since the 5-year survival rate of metastatic CRC is only about 10%, it is important to receive detailed information on molecular level regarding its carcinogenesis and progression and to search for new effective therapy concepts. Although modern treatment schemes have resulted in prolonged median survival of patients, the overall prognosis is still poor. Because of high apoptotic resistance and metastatic potential conventional chemotherapeutic concepts are often ineffective in the treatment of CRC, or are associated with severe side effects. Therefore, research efforts are currently focusing on the identification of novel target molecules. In line with this notion, drug discovery projects aiming to develop effective and isoform-specific CK1 inhibitors have drawn considerable interest. Members of the serine/threonine-specific CK1 family are evolutionary highly conserved and ubiquitously expressed in eukaryotic organisms. So far, seven distinct genes encoding mammalian CK1 isoforms a, b, g1, g2, g3, d, E and various splice variants have been characterized. CK1 isoforms play major regulatory

Germline Genetic Variants in the Wnt/β-Catenin Pathway as Predictors of Colorectal Cancer Risk

“…Other cis-eQTL effects for CSNK1D variants include rs9901910 for DCXR (dicarbonyl/L-xylulose reductase) and rs7503429 for SLC16A3 , DCXR and STRA13. Although several variants in our study were predicted to have direct functional effects on expression of the aforementioned genes, it has been reported that mutations in CSNK1D, encoding for a serine-threonine protein component of the beta-catenin destruction complex, can promote the development of CRC (37). CSNK1D is located close to SLC16A3 , encoding a monocarboxylate transporter, with potential for overlapping regulatory elements.…”

Newly Developed CK1-Specific Inhibitors Show Specifically Stronger Effects on CK1 Mutants and Colon Cancer Cell Lines

“…As already described in previous studies, mutations in the coding sequence for CK1δ cannot only influence the activity of the enzyme but also the binding and efficacy of small molecule inhibitors [2,21]. Therefore, the sensitivity of CK1δ hyperactive mutants toward different CK1-specific inhibitors was analyzed and residual kinase activities upon inhibitor treatment are summarized in Table 2.…”

“…Dysregulation of CK1δ expression and/or activity has been observed in different types of disorders, including cancer. So far, different CK1δ mutations have been already identified and seem to have a higher oncogenic potential in comparison to CK1δ wild type [1,2]. Recently, the CK1δ T67S mutant has been identified in colon and rectal cancer (CRC) and this mutant showed increased in vitro kinetics and is associated with increased cell proliferation and tumor growth in both cell culture and in a subcutaneous tumor xenotransplantation mouse model [2].…”

“…So far, different CK1δ mutations have been already identified and seem to have a higher oncogenic potential in comparison to CK1δ wild type [1,2]. Recently, the CK1δ T67S mutant has been identified in colon and rectal cancer (CRC) and this mutant showed increased in vitro kinetics and is associated with increased cell proliferation and tumor growth in both cell culture and in a subcutaneous tumor xenotransplantation mouse model [2]. Another CK1δ mutant, CK1δ R324H , has been observed in adenomas of intestinal mucosa and seems to have carcinogenic potential, which may influence tumorigenic development [3].…”

Facts and myths of selective casein kinase 1ε einhibition

“…In contrast, other studies reported that a significant number of patients with a high level of CK1ε expression are the ones that have better prognosis and survival [8,22,30]. Nevertheless, this source of contradiction must be properly interpreted.…”