396 POSTER Broad spectrum and potent anti tumor activity of YM155, a novel small moiecule survivin suppressant, against a large scale panel of human tumor cell lines

Colorectal cancer is thought to originate in the expansion of colonic crypt cells as a result of aberrant gene expression caused by transcription factors of the T-cell factor (TCF)/β-catenin family. Survivin is a bifunctional regulator of cell death and cell proliferation expressed during embryonic development but undetectable in healthy adult tissues and re-expressed in many cancers, including colorectal cancer.We investigated gene expression by promoter analysis, mutagenesis, and electrophoretic mobility shift assay in colorectal cancer cells. Survivin expression in human and mouse embryonic intestine was determined by insitu hybridisation and immunohistochemistry. Changes in apoptosis were monitored in cell lines engineered to express stabilising mutations in β catenin.TCF/β catenin stimulated a six-fold to 12-fold increased expression of the survivin gene in colorectal cancer cells. Three TCF-binding elements (TBE) in the survivin promoter were occupied by nuclear factors in colorectal cancer cells, and mutagenesis of the two proximal TBE sites abolished survivin gene expression by 75–79%. Strongly expressed at the bottom of human and mouse embryonic intestinal crypts, expression of survivin was lost in TCF-4 knockout animals, and a TCF-4 dominant negative mutant blocked survivin gene transcription in colorectal cancer cells. Expression of non-destructible β catenin mutants increased survivin expression and protected against ultraviolet-Binduced apoptosis.Stimulation of survivin expression by TCF/β catenin might impose a stem cell-like phenotype to colonic crypt epithelium coupling enhanced cell proliferation with resistance to apoptosis, and contribute to the molecular pathogenesis of colorectal cancer.