title: 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 CK1δ and ɛ is changed in colorectal tumors compared to normal bowel epithelium, and high CK1ɛ expression levels significantly correlate with prolonged patients' survival. In addition to changes in CK1δ and ɛ expression, mutations within exon 3 of CK1δ were detected in colorectal tumors. These mutations influence ATP binding resulting in changes in kinetic parameters of CK1δ. Overexpression of these mutants in HT29 cells alters their ability to grow anchorage independently. Consistent with these results, these CK1δ 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.
authors.affiliation: Department of General and Visceral Surgery, Ulm University Hospital, Albert-Einstein-Allee 23, 89081, Ulm, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Richter
authors.forename: Kalim
authors.initials: K
authors.lastname: Ullah
authors.forename: Pengfei
authors.initials: P
authors.lastname: Xu
authors.forename: Vanessa
authors.initials: V
authors.lastname: Alscher
authors.forename: Annette
authors.initials: A
authors.lastname: Blatz
authors.forename: Christian
authors.initials: C
authors.lastname: Peifer
authors.forename: Jakob
authors.initials: J
authors.lastname: Halekotte
authors.forename: Johann
authors.initials: J
authors.lastname: Leban
authors.forename: Daniel
authors.initials: D
authors.lastname: Vitt
authors.forename: Karlheinz
authors.initials: K
authors.lastname: Holzmann
authors.forename: Vasiliy
authors.initials: V
authors.lastname: Bakulev
authors.forename: Lorenzo A
authors.initials: LA
authors.lastname: Pinna
authors.forename: Doris
authors.initials: D
authors.lastname: Henne-Bruns
authors.forename: Andreas
authors.initials: A
authors.lastname: Hillenbrand
authors.forename: Marko
authors.initials: M
authors.lastname: Kornmann
authors.forename: Frank
authors.initials: F
authors.lastname: Leithäuser
authors.forename: Joachim
authors.initials: J
authors.lastname: Bischof
authors.forename: Uwe
authors.initials: U
authors.lastname: Knippschild
mesh_terms: D000368:Aged; D000818:Animals; D015153:Blotting, Western; D048149:Casein Kinase 1 epsilon / Q000235:genetics* / Q000378:metabolism; D048148:Casein Kinase Idelta / Q000235:genetics* / Q000378:metabolism; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D019073:HT29 Cells; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000235:genetics
chemical_list: D048149:Casein Kinase 1 epsilon; D048148:Casein Kinase Idelta
keywords: Casein Kinase 1 (CK1); colorectal cancer; kinase activity; mutation; oncogenic potential