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Effects of altered expression and activity levels of CK1δ and ɛ on tumor growth and survival of colorectal cancer patients
Author(s) -
Richter Julia,
Ullah Kalim,
Xu Pengfei,
Alscher Vanessa,
Blatz Annette,
Peifer Christian,
Halekotte Jakob,
Leban Johann,
Vitt Daniel,
Holzmann Karlheinz,
Bakulev Vasiliy,
Pinna Lorenzo A.,
HenneBruns Doris,
Hillenbrand Andreas,
Kornmann Marko,
Leithäuser Frank,
Bischof Joachim,
Knippschild Uwe
Publication year - 2014
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.29346
Subject(s) - colorectal cancer , cancer research , cell growth , biology , mouse model of colorectal and intestinal cancer , cancer , tumor progression , gene isoform , mutant , medicine , gene , genetics
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.