ABSTRACT
Deregulated global mRNA translation is an emerging feature of cancer cells. Oncogenic transformation in colorectal cancer (CRC) is driven by mutations in APC, KRAS, SMAD4, and TP53, known as the adenoma-carcinoma sequence (ACS). Here we introduce each of these driver mutations into intestinal organoids to show that they are modulators of global translational capacity in intestinal epithelial cells. Increased global translation resulting from loss of Apc expression was potentiated by the presence of oncogenic KrasG12D Knockdown of Smad4 further enhanced global translation efficiency and was associated with a lower 4E-BP1-to-eIF4E ratio. Quadruple mutant cells with additional P53 loss displayed the highest global translational capacity, paralleled by high proliferation and growth rates, indicating that the proteome is heavily geared toward cell division. Transcriptional reprogramming facilitating global translation included elevated ribogenesis and activation of mTORC1 signaling. Accordingly, interfering with the mTORC1/4E-BP/eIF4E axis inhibited the growth potential endowed by accumulation of multiple drivers. In conclusion, the ACS is characterized by a strongly altered global translational landscape in epithelial cells, exposing a therapeutic potential for direct targeting of the translational apparatus.
Subject(s)
Adenoma/genetics , Carcinoma/genetics , Mutation/ethics , Protein Biosynthesis/genetics , Adenoma/metabolism , Animals , Carcinoma/metabolism , Colorectal Neoplasms/genetics , Colorectal Neoplasms/metabolism , HEK293 Cells , Humans , Intestines/cytology , Mechanistic Target of Rapamycin Complex 1/genetics , Mechanistic Target of Rapamycin Complex 1/metabolism , Mice , Mice, Transgenic , Organoids/metabolism , Signal Transduction , Tissue Culture TechniquesABSTRACT
Crohn's disease, ulcerative colitis, and pouchitis after ileal pouch anal anastomosis in ulcerative colitis patients are often refractory to standard therapy. Over the last decade, the rational to use probiotics and its beneficial efficacy in the treatment of chronic inflammatory bowel disease (IBD) is increasingly under scrutiny. Although it has become clear that intestinal epithelial-mucosal immune interactions and enteric bacteria play a critical role in the development of IBD, the substantial clinical efficacy of probiotics in these disorders is less evident. This review outlines the clinical studies regarding probiotics before October 2007. These studies formed the foundation of probiotic clinical trials in IBD, but they also indicated the need of larger and better-controlled studies than the past experimental approaches. Furthermore, this review also examines in-depth the probiotic clinical trials published between 2007 and December 2010, providing new insights into the role of probiotics for inducing and maintaining remission of IBD, and highlighting some of the breakthroughs, especially regarding induction of remission for ulcerative colitis.
