glycogen and Colorectal-Neoplasms

Coordination of gene expression with nutrient availability supports proliferation and homeostasis and is shaped by protein acetylation. Yet how physiological/pathological signals link acetylation to specific gene expression programs and whether such responses are cell-type-specific is unclear. AMP-activated protein kinase (AMPK) is a key energy sensor, activated by glucose limitation to resolve nutrient supply-demand imbalances, critical for diabetes and cancer. Unexpectedly, we show here that, in gastrointestinal cancer cells, glucose activates AMPK to selectively induce EP300, but not CREB-binding protein (CBP). Consequently, EP300 is redirected away from nuclear receptors that promote differentiation towards β-catenin, a driver of proliferation and colorectal tumorigenesis. Importantly, blocking glycogen synthesis permits reactive oxygen species (ROS) accumulation and AMPK activation in response to glucose in previously nonresponsive cells. Notably, glycogen content and activity of the ROS/AMPK/EP300/β-catenin axis are opposite in healthy versus tumor sections. Glycogen content reduction from healthy to tumor tissue may explain AMPK switching from tumor suppressor to activator during tumor evolution.

Topics: AMP-Activated Protein Kinases; Animals; beta Catenin; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; CREB-Binding Protein; E1A-Associated p300 Protein; Enzyme Activation; Glucose; Glycogen; Mice, Inbred C57BL; Protein Binding; Reactive Oxygen Species; Signal Transduction

Topics: Amino Acid Transport System ASC; Cell Proliferation; Cell Transformation, Neoplastic; Colonic Neoplasms; Colorectal Neoplasms; Computational Biology; Exosomes; Fibroblasts; Fluorescent Antibody Technique; Glucose Transporter Type 1; Glycogen; Humans; Lactic Acid; Minor Histocompatibility Antigens; Proteomics; Tumor Microenvironment

The present study assessed whether and how tumor cells undergoing hypoxia contribute to disease progression after moving to areas with different oxygen conditions.. Human colorectal carcinoma HCT116 cells cultured under mild hypoxia were subjected to in vivo experiments using transfer to immunodeficient murine recipients and to in vitro experiments using pharmacological inhibition of fatty acid β-oxidation (FAO).. Bone involvement and hepatic metastases were accelerated in transfer models of hypoxically cultured HCT116 cells. Hypoxic HCT116 cells exhibited FAO-dependent glycogen synthesis. FAO-dependent and -independent induction of gene expression also occurred under hypoxia. The distribution of glucose transporter 1 expression compared with heme oxygenase 1 expression in HCT116 cell spheroids seemed consistent with differential dependence of hypoxic expression of these molecules on FAO.. These results provide insights into the contribution of hypoxia to tumor progression and the relevance of FAO.

Topics: Animals; Colorectal Neoplasms; Fatty Acids; Gene Expression Regulation, Neoplastic; Glucose Transporter Type 1; Glycogen; HCT116 Cells; Heme Oxygenase-1; Humans; Mice; Oxidation-Reduction; Oxygen; Spheroids, Cellular; Tumor Hypoxia; Xenograft Model Antitumor Assays

To characterise differences between three widely used colorectal cancer cell lines using ultrastructural selective staining for glycogen to determine variation in metastatic properties.. Transmission electron microscopy was used in this investigation to help identify intracellular structures and morphological features which are precursors of tumor invasion. In addition to morphological markers, we used selective staining of glycogen as a marker for neoplastic cellular proliferation and determined whether levels of glycogen change between the three different cell lines.. Ultrastructural analysis revealed morphological differences between the cell lines, as well as differentiation into two sub-populations within each cell line. Caco-2 cells contained large glycogen deposits as well as showing the most obvious morphological changes between the two sub-populations. SW480 cells also contained large glycogen stores as well as deep cellular protrusions when grown on porous filter membranes. HT-29 cells had trace amounts of glycogen stores with few cellular projections into the filter pores and no tight junction formation.. Morphology indicative of metastatic properties coincided with larger glycogen deposits, providing strong evidence for the use of selective staining to determine the neoplastic properties of cells.

Topics: Caco-2 Cells; Colorectal Neoplasms; Glycogen; HT29 Cells; Humans; Microscopy, Electron, Transmission; Staining and Labeling

In this study, we quantitatively measured glycogen levels in tissue samples obtained from tumors, regions adjacent to tumor, and regions of normal colorectum to determine whether the levels were related to cell cycle and cancer growth. Glycogen levels were analyzed in relation to histopathological factors, (tumor size and stage of disease) and cell cycle progression. The glycogen level was found to be highest in the cancer tissue, lower in normal tissue, and lowest in the adjacent tissue. The difference in glycogen level between the cancer tissue and the other two regions was significant (P < 0.05). There was a negative correlation between glycogen level and tumor size, but it was not significant. The level of glycogen in cancer tissues decreased as the stage of the disease progressed, but a significant difference was not found between stages. There was a negative correlation between the glycogen level and the proliferation index. There was a positive correlation between the glycogen level and the proportion of cancer cells in G1 phase, while there was a negative correlation with S and G2M phases. Glycogen levels were highest in cancers with a high proportion of cells in G1, and decreased with progression to S phase. It may be that glycogen is utilized in the progression to S phase, and the cancer tissues are supplied with glycogen from the tumors themselves as well as their adjacent tissues. Cancer growth may be inhibited by artificial control of the glycogen level in the G1 phase of cancer cells.

Topics: Adenocarcinoma; Aged; Cell Cycle; Colon; Colorectal Neoplasms; DNA; Female; Glycogen; Humans; Male; Middle Aged; Mitotic Index; Rectum; Spectroscopy, Fourier Transform Infrared