Cancer cells alter their metabolism for the production of precursors of macromolecules. However, the control mechanisms underlying this reprogramming are poorly understood. Here we show that metabolic reprogramming of colorectal cancer is caused chiefly by aberrant MYC expression. Multiomics-based analyses of paired normal and tumor tissues from 275 patients with colorectal cancer revealed that metabolic alterations occur at the adenoma stage of carcinogenesis, in a manner not associated with specific gene mutations involved in colorectal carcinogenesis. MYC expression induced at least 215 metabolic reactions by changing the expression levels of 121 metabolic genes and 39 transporter genes. Further, MYC negatively regulated the expression of genes involved in mitochondrial biogenesis and maintenance but positively regulated genes involved in DNA and histone methylation. Knockdown of MYC in colorectal cancer cells reset the altered metabolism and suppressed cell growth. Moreover, inhibition of MYC target pyrimidine synthesis genes such as CAD, UMPS, and CTPS blocked cell growth, and thus are potential targets for colorectal cancer therapy.ne of the prominent characteristics of rapidly growing tumor cells is their capacity to sustain high rates of glycolysis for ATP generation irrespective of oxygen availability, termed the Warburg effect (1). Recent studies have shown that cancer cells shift metabolic pathways to facilitate the uptake and incorporation of abundant nutrients, such as glucose and glutamine (2, 3), into cell building blocks, such as nucleotides, amino acids, and lipids, that are essential for highly proliferating cells (4). This seems to be a universal characteristic of highly malignant tumors (5), independent of their carcinogenetic origin (6). Understanding how cancer cells reprogram metabolism can stimulate the development of new approaches in cancer therapy.Although there is now substantial information about how these pathways are regulated, most existing studies on cancer metabolism have used in vitro cell lines. In addition to genetic and epigenetic alterations, altered tumor microenvironment (e.g., blood flow, oxygen and nutrient supply, pH distribution, redox state, and inflammation) plays a profound role in modulating tumor cell metabolism (7-9). Therefore, a systematic characterization of in vivo metabolic pathways was deemed necessary to understand how metabolic phenotypes are regulated in intact human tumors.Here we applied multiomics-based approaches [i.e., metabolomics, target sequencing of cancer-related genes, transcriptomics, and methylated DNA immunoprecipitation sequencing (MeDIPseq)] to paired normal and tumor tissues obtained from 275 patients with colorectal cancer (CRC) and uncovered the details of which factors contributed, and when they contributed, to metabolic reprogramming in colorectal cancer. The results were confirmed by analysis of colorectal tissue from Apc mutant mice and cancer cell lines.

The unfolded protein response (UPR), which is activated when unfolded or misfolded proteins accumulate in the endoplasmic reticulum, has been implicated in the normal physiology of immune defense and in several human diseases including diabetes, cancer, neurodegenerative disease, and inflammatory disease. In this study, we found that the nervous system controlled the activity of a non-canonical UPR pathway required for innate immunity in Caenorhabditis elegans. OCTR-1, a putative octopamine G protein-coupled catecholamine receptor (GPCR, G protein–coupled receptor), functioned in sensory neurons designated ASH and ASI to actively suppress innate immune responses by down-regulating the expression of non-canonical UPR genes pqn/abu in non-neuronal tissues. Our findings suggest a novel molecular mechanism by which the nervous system may sense inflammatory responses and respond by controlling stress-response pathways at the organismal level.

Recent studies have revealed that TAK1 kinase is an essential intermediate in several innate immune signaling pathways. In this study, we investigated the role of TAK1 signaling in maintaining intestinal homeostasis by generating enterocytes-specific constitutive and inducible gene deleted TAK1 mice. We found that enterocyte-specific constitutive TAK1 deleted mice spontaneously developed intestinal inflammation as observed by histological analysis and enhanced expression of IL-1β, MIP2 and IL-6 around the time of birth, which was accompanied by significant enterocytes apoptosis. When TAK1 was deleted in the intestinal epithelium of 4-week-old mice using an inducible knockout system, enterocytes underwent apoptosis and intestinal inflammation developed within 2–3 days following the initiation of gene deletion. We found that enterocytes apoptosis and intestinal inflammation were strongly attenuated when enterocyte-specific constitutive TAK1 deleted mice were crossed to TNF receptor 1 (TNFR1)−/− mice. However, these mice later (>14 days) developed ileitis and colitis. Thus, TAK1 signaling in enterocytes is essential for preventing TNF-dependent epithelium apoptosis and the TNF-independent development of ileitis and colitis. We propose that aberration in TAK1 signaling might disrupt intestinal homeostasis and favor the development of inflammatory disease.

The intestinal epithelium is constantly exposed to inducers of reactive oxygen species (ROS), such as commensal microorganisms. Levels of ROS are normally maintained at nontoxic levels, but dysregulation of ROS is involved in intestinal inflammatory diseases.In this article, we report that TGF-b-activated kinase 1 (TAK1) is a key regulator of ROS in the intestinal epithelium. tak1 gene deletion in the mouse intestinal epithelium caused tissue damage involving enterocyte apoptosis, disruption of tight junctions, and inflammation. Disruption of TNF signaling, which is a major intestinal damage inducer, rescued the inflammatory conditions but not apoptosis or disruption of tight junctions in the TAK1-deficient intestinal epithelium, suggesting that TNF is not a primary inducer of the damage noted in TAK1-deficient intestinal epithelium. We found that TAK1 deficiency resulted in reduced expression of several antioxidant-responsive genes and reduced the protein level of a key antioxidant transcription factor NF-E2-related factor 2, which resulted in accumulation of ROS. Exogenous antioxidant treatment reduced apoptosis and disruption of tight junctions in the TAK1-deficient intestinal epithelium. Thus, TAK1 signaling regulates ROS through transcription factor NF-E2-related factor 2, which is important for intestinal epithelial integrity. The Journal of Immunology, 2010, 185: 4729-4737.I ntegrity of the epithelial barrier is essential for preventing invasion of microorganisms and the development of chronic inflammatory conditions in the intestine. A single layer of enterocytes separates the lamina propria from the gut lumen, thereby functioning as a physical barrier. Enterocytes are derived from intestinal epithelial stem cells that are localized to the crypts. Proliferating enterocytes differentiate and migrate toward the villus tips in the small intestine (1). Enterocytes undergo apoptosis only at the apical component of the villi. Although the intestine is constantly exposed to high levels of cell-death inducers, such as TNF and bacteria-derived stressors, enterocytes are resistant to those inducers and survive until they reach the tip of the villus. Dysregulated apoptosis during the periods of proliferation and migration disrupts the intestinal barrier. In addition to enterocyte survival, tightly connected enterocyte-enterocyte junctions (tight junctions) are essential to form the physical barrier (2). Recently, it has become evident that commensal bacteria play a protective role in intestinal epithelial barrier function (3, 4). For example, depletion of commensal bacteria greatly increases sensitivity to stress-induced intestinal damage (4). Ablation of TLR signaling from commensal bacteria disrupts the integrity of tight junctions in enterocytes (5). Therefore, commensal bacteria-derived cell signaling is likely to play a crucial role in cell survival and regulation of tight junctions in enterocytes. However, the intracellular signaling pathways that maintain enterocyte survival and tight junctions remain elusiv...