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Genetic pathways, prevention, and treatment of sporadic colorectal cancer

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Genetic pathways, prevention, and treatment of sporadic colorectal cancer ABSTRACT Epithelial cancer of the colon and rectum, also known as colorectal cancer (CRC), results from a progressive accumulation of genetic and epigenetic alterations that lead to uncontrolled growth of colonocytes, the cells lining the colon and rectum. CRC is the second leading cause of cancer-related deaths and the third most common cancer in men and in women in the U.S. Of all the patients diagnosed with CRC every year, it is estimated that the vast majority of CRCs are non-hereditary “sporadic cancers” with no apparent evidence of an inherited component. Sporadic CRC results from the cumulative effects of multiple genetic and epigenetic alterations caused by somatic mutations, which may themselves be the indirect result of several environmental factors. This review examines our current understanding of the major genetic alterations leading to colon cancer, options for prevention and early detection of CRC,
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RECK-Mediated Suppression of Tumor Cell Invasion Is Regulated by Glycosylation in Human Tumor Cell Lines

RECK-Mediated Suppression of Tumor Cell Invasion Is Regulated by Glycosylation in Human Tumor Cell Lines Abstract RECK, a glycosylphosphatidylinositol (GPI)–anchored glycoprotein, negatively regulates matrix metalloproteinases (MMP), such as MMP-9, and inhibits tumor invasion and metastasis. The predicted amino acid sequence of human RECK includes five putative N-glycosylation sites; however, the precise biochemical role of glycosylated RECK remains unknown. In this study, we examined the link between glycosylation and the function of RECK in human tumor cell lines. RECK protein was glycosylated at Asn 86 , Asn 200 , Asn 297 , and Asn 352  residues but not at the Asn 39  residue in HT1080 cells. Although the glycosylation of these asparagine sites did not play a role in the cell surface localization of RECK as a GPI-anchored protein, the glycosylation of RECK Asn 297  residue was involved in the suppression of MMP-9 secretion and Asn 352  residue was necessary to inhibit MMP-2 activati
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Cystine-Glutamate Transporter SLC7A11 in Cancer Chemosensitivity and Chemoresistance

Cystine-Glutamate Transporter  SLC7A11  in Cancer Chemosensitivity and Chemoresistance Abstract SLC7A11  ( xCT ), together with  SLC3A2  ( 4F2hc ), encodes the heterodimeric amino acid transport system x c − , which mediates cystine-glutamate exchange and thereby regulates intracellular glutathione levels. We used microarrays to analyze gene expression of transporters in 60 human cancer cell lines used by the National Cancer Institute for drug screening (NCI-60). The expression of  SLC7A11  showed significant correlation with that of  SLC3A2  ( r  = 0.66), which in turn correlated with  SLC7A5  ( r  = 0.68), another known partner for  SLC3A2 , and with  T1A-2  ( r  = 0.60; all  P  < 0.0001). Linking expression of  SLC7A11  with potency of 1,400 candidate anticancer drugs identified 39 showing positive correlations, e.g., amino acid analogue,  l -alanosine, and 296 with negative correlations, e.g., geldanamycin. However, no significant correlation was observed with the geldanamycin a
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Reactive Oxygen Species Regulate Caspase Activation in Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Resistant Human Colon Carcinoma Cell Lines

Reactive Oxygen Species Regulate Caspase Activation in Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Resistant Human Colon Carcinoma Cell Lines Abstract The effects of reactive oxygen species (ROS) on tumor necrosis factor–related apoptosis–inducing ligand (TRAIL)–induced apoptosis in solid cancers have yet to be clearly defined. In this study, we found that the classic uncoupler of oxidative phosphorylation, carbonyl cyanide  m -chlorophenylhydrazone (CCCP), induced a reduction in Δ Ψ m  and generation of ROS. This uncoupling effect enhanced TRAIL-induced apoptosis in TRAIL-resistant human colon carcinoma cell lines (RKO, HT29, and HCT8). Sensitization was inhibited by benzyloxycarbonyl-valine-alanine-aspartate fluoromethylketone, indicating the requirement for caspase activation. CCCP per se did not induce apoptosis or release of proapoptotic factors from mitochondria. Generation of ROS by CCCP was responsible for TRAIL-induced Bax and caspase activation because scavenging
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GSK-3 as potential target for therapeutic irvention in cancer

GSK-3 as potential target for therapeutic irvention in cancer Abstract The serine/threonine kinase glycogen synthase kinase-3 (GSK-3) was initially identified and studied in the regulation of glycogen synthesis. GSK-3 functions in a wide range of cellular processes. Aberrant activity of GSK-3 has been implicated in many human pathologies including: bipolar depression, Alzheimer's disease, Parkinson's disease, cancer, non-insulin-dependent diabetes mellitus (NIDDM) and others. In some cases, suppression of GSK-3 activity by phosphorylation by Akt and other kinases has been associated with cancer progression. In these cases, GSK-3 has tumor suppressor functions. In other cases, GSK-3 has been associated with tumor progression by stabilizing components of the beta-catenin complex. In these situations, GSK-3 has oncogenic properties. While many inhibitors to GSK-3 have been developed, their use remains controversial because of the ambiguous role of GSK-3 in cancer development. In t
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Intermittentsupplementation with rapamycin as a dietary restriction mimetic

Intermittent supplementation with rapamycin as a dietary restriction mimetic Aging is a complex process associated with accumulation of damage, loss of function and increased vulnerability to disease, leading ultimately to death. Despite the complicated etiology of aging, an important discovery of recent years has been that simple genetic alterations can cause a substantial increase in healthy lifespan in laboratory model organisms [1]. Many of these longevity-extending mutations down-regulate the activity of the mTOR/S6K pathway [2-5] suggesting that reduced Tor/S6K signaling promotes entry into alternative phases normally entered during periods of starvation. In fact, dietary restriction (DR), a reduction in food intake without malnutrition, lowers Tor/S6K signaling and extends the average and maximum life span of a variety of organisms including yeast, flies, worms, fish, and rodents [1]. In both rodents and monkeys, it delays loss of function and reduces the incidence of major dise
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GSK-3 as potential target for therapeutic irvention in cancer

GSK-3 as potential target for therapeutic irvention in cancer Abstract The serine/threonine kinase glycogen synthase kinase-3 (GSK-3) was initially identified and studied in the regulation of glycogen synthesis. GSK-3 functions in a wide range of cellular processes. Aberrant activity of GSK-3 has been implicated in many human pathologies including: bipolar depression, Alzheimer's disease, Parkinson's disease, cancer, non-insulin-dependent diabetes mellitus (NIDDM) and others. In some cases, suppression of GSK-3 activity by phosphorylation by Akt and other kinases has been associated with cancer progression. In these cases, GSK-3 has tumor suppressor functions. In other cases, GSK-3 has been associated with tumor progression by stabilizing components of the beta-catenin complex. In these situations, GSK-3 has oncogenic properties. While many inhibitors to GSK-3 have been developed, their use remains controversial because of the ambiguous role of GSK-3 in cancer development. In t
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