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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aberrant activation of the Wnt pathway is observed in numerous cancers, and is particularly important in colon cancer. We demonstrate that Rac1 GTPase can significantly increase the signaling activity of beta-catenin in cells with inherent dysregulation of the canonical Wnt signaling pathway. Expression of dominant-negative (N17)Rac1 mutant in colon cancer cells caused a marked inhibition of Wnt signaling, as determined by the TCF/LEF-responsive (TOPFLASH) transcription assay. Expression of a constitutively active (V12)Rac1 mutant caused up to 40-fold induction from the TOPFLASH promoter, and this was dependent on the presence of stabilized beta-catenin. This induction was completely blocked by the expression of dominant-negative TCF-4, suggesting that beta-catenin and TCF-4 complex formation is required for Rac1-mediated transcription. Furthermore, we show that Cyclin D1, an important biological Wnt target gene, is regulated by Rac1 in a beta-catenin/TCF-dependent manner. We observed that Rac1 co-immunoprecipitates with beta-catenin and TCF-4 only in its active GTP-bound form. Both cell fractionation studies and fluorescence microscopy indicate that overexpression of V12Rac1 results in increased cytosolic and nuclear expression of beta-catenin. Interestingly, mutation of the polybasic region of Rac1, which prevents its nuclear localization, also caused an appreciable decrease in nuclear localization of beta-catenin, and effectively abolished its beta-catenin-dependent transcription co-activator function. Taken together, our data demonstrate a novel mechanism of Wnt pathway regulation whereby activation of Rac1 amplifies the signaling activity of stabilized/mutated beta-catenin by promoting its accumulation in the nucleus, and synergizing with beta-catenin to augment TCF/LEF-dependent gene transcription.
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PMID:Cross-talk between Rac1 GTPase and dysregulated Wnt signaling pathway leads to cellular redistribution of beta-catenin and TCF/LEF-mediated transcriptional activation. 1537 99

Macroautophagy or autophagy is an ubiquitous and conserved degradative pathway of cytosolic components, macromolecules or organelles, into the lysosome. By using biochemical and microscopic methods, which allow one to measure the rate of autophagy, the role of two regulators of Gi3 protein activity, activator of G-protein-signaling-3 (AGS3) and Galpha-interacting protein (GAIP), was studied in the control of autophagy in human colon cancer HT-29 cells. In HT-29 cells, autophagy is under the control of the Gi3 protein and, when bound to the GTP, the Galphai3 protein inhibits autophagy, whereas it stimulates autophagy when bound to the GDP. GAIP, which enhances the intrinsic GTPase-activating protein activity of the Galphai3 protein, stimulates autophagy by favoring the GDP-bound form of Galphai3. We showed that GAIP is phosphorylated on its serine 151 and that this phosphorylation is dependent on the presence of amino acids that modulate Raf-1 activity, the kinase upstream of Erk1/2. AGS3, a guanine nucleotide dissociation inhibitor, stimulates autophagy by binding Galphai3 proteins. The intracellular localization of AGS3 (Golgi apparatus and endoplasmic reticulum, two membranes known to be at the origin of autophagosomes) is consistent with its role in autophagy.
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PMID:Analyses of Galpha-interacting protein and activator of G-protein-signaling-3 functions in macroautophagy. 1548 68

Inflammatory bowel diseases are associated with increased risk of developing colon cancer. A possible role of the pro-inflammatory leukotriene D4 (LTD4) in this process has been implicated by the findings that LTD4 can signal increased proliferation and survival, both hallmarks of a cancer cell, in non-transformed intestinal epithelial cells. Here we make the novel finding that LTD4 can also signal increased motility in these cells. In parallel, we found that LTD4 induced a simultaneous transient 10-fold increase in Rac but not Cdc42 activity. These data were also supported by the ability of LTD4 to activate the Rac GDP/GTP exchange factor Vav2. Further, LTD4 triggered a 3-fold transient increase in phosphatidylinositol 3-kinase (PI3K) phosphorylation, a possible upstream activator of the Vav2/Rac signaling pathway. The activation of Rac was blocked by the PI3K inhibitors LY294002 and wortmannin and by transfection of a kinase-negative mutant of PI3K or a dominant-negative form of Vav2. Furthermore, Rac was found to co-localize with actin in LTD4-generated membrane ruffles that were formed by a PI3K-dependent mechanism. In accordance, the inhibition of the PI3K and Rac signaling pathway also blocked the LTD4-induced migration of the intestinal cells. The present data reveal that an inflammatory mediator such as LTD4 cannot only increase proliferation and survival of non-transformed intestinal epithelial cells but also, via a PI3K/Rac signaling pathway, trigger a motile response in such cells. These data demonstrate the capacity of inflammatory mediators to participate in the process by which inflammatory bowel conditions increase the risk for colon cancer development.
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PMID:The pro-inflammatory mediator leukotriene D4 induces phosphatidylinositol 3-kinase and Rac-dependent migration of intestinal epithelial cells. 1565 50

The sodium-selective amiloride-sensitive epithelial sodium channel (ENaC) mediates electrogenic sodium re-absorption in tight epithelia. ENaC expression at the plasma membrane requires regulated transport, processing, and macromolecular assembly of subunit proteins in a defined and highly compartmentalized manner. Ras-related Rab GTPases monitor these processes in a highly regulated sequence of events. In order to evaluate the role of Rab proteins in ENaC function, Rab4 wild-type (WT), the GTPase-deficient mutant Rab4Q67L, and the dominant negative GDP-locked mutant Rab4S22N were over-expressed in the colon cancer cell line, HT-29 and amiloride-sensitive currents were recorded. Rab4 over-expression inhibited amiloride-sensitive currents. The effect was reversed by introducing Rab4-neutralizing antibody and Rab4 specific SiRNA. The GDP-locked Rab4 mutant inhibited, while GTPase-deficient mutant moderately stimulated amiloride-sensitive currents. Active status of Rab4 was confirmed by GTP overlay assay, while its expression was verified by Western blotting. Immunoprecipitation and pull-down assay suggest protein-protein interaction between Rab4 and ENaC. In addition, the functional modulation coincides with concomitant changes in ENaC expression at the cell surface and in intracellular pool. We propose that Rab4 is a critical element that regulates ENaC function by mechanisms that include GTP-GDP status, recycling, and expression level. Our observations imply that channel expression in apical membranes of epithelial cell system incorporates RabGTPase as an essential determinant of channel function and adds an exciting paradigm to ENaC therapeutics.
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PMID:Rab4 GTP/GDP modulates amiloride-sensitive sodium channel (ENaC) function in colonic epithelia. 1638 71

Aberrant crypt foci (ACF) are collections of abnormal colonic crypts with heterogeneous molecular and pathologic characteristics. Large and dysplastic ACF are putative precursors of colon cancer with neoplastic risk related to increased proliferation. In this study, we examined the role of epidermal growth factor receptor (EGFR) signaling in regulating ACF proliferation. Using magnification chromoendoscopy, we collected large ACF with endoscopic features of dysplasia and separately biopsied adjacent mucosa. Transcript levels were measured by real-time PCR, proteins were assessed by Western blotting, and levels were expressed as fold changes of adjacent mucosa. K-ras and B-Raf mutations were assessed by PCR and Ras activation by the ratio Ras-GTP / (Ras-GTP + Ras-GDP). At the RNA level, 38% of ACF were hyperproliferative, with proliferating cell nuclear antigen (PCNA) mRNA >/=2-fold of adjacent mucosa. Hyperproliferative ACF had significantly increased mRNA levels of EGFR (6.0 +/- 1.7-fold), transforming growth factor-alpha (14.4 +/- 5.0-fold), heparin-binding EGF-like growth factor (4.5 +/- 1.4-fold), cyclin D1 (4.6 +/- 0.7-fold), and cyclooxygenase-2 (COX-2; 9.3 +/- 4.2-fold; P < 0.05). At the protein level, 46% of ACF were hyperproliferative (PCNA, 3.2 +/- 1.2-fold). In hyperproliferative ACF, 44% possessed significant increases in four EGFR signaling components: EGFR (9.5 +/- 1.3-fold), phosphoactive ErbB2 (2.6 +/- 0.4-fold), phosphoactive extracellular signal-regulated kinase (3.7 +/- 1.1-fold), and cyclin D1 (3.4 +/- 0.8-fold; P < 0.05). Ras was activated in 46% of ACF (3.2 +/- 0.4-fold; P < 0.05), but K-ras mutations were present in only 7% of ACF. In contrast to COX-2 mRNA, the protein was not increased in hyperproliferative ACF. In summary, we have shown that ACF with up-regulated PCNA possess increased EGFR signaling components that likely contribute to the enhanced proliferative state of dysplastic-appearing ACF.
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PMID:Epidermal growth factor receptor signaling is up-regulated in human colonic aberrant crypt foci. 1674 Jul 3

The HRAS-like suppressor 2 (HRASLS2) gene belongs to the H-REV107 gene family involved in the regulation of cell growth and differentiation. HRASLS2 is expressed at high levels in normal tissues of the small intestine, kidney, and trachea. We cloned HRASLS2 cDNA from human SW480 colon cancer cells. Most wild-type, and some N- and C-terminal truncated HRASLS2 (HRASLS2DeltaNDeltaC) were expressed as a granular pattern located at perinuclear region in HtTA cervical cancer cells, while truncation at the C-terminus only (HRASLS2DeltaC) resulted in a diffuse pattern. Wild-type HRASLS2 significantly suppressed colony formation of HeLa and HCT116 cells. HRASLS2DeltaNDeltaC significantly inhibited colony formation of HCT116 cells, but HRASLS2DeltaC did not affect cell growth. HRASLS2 suppressed the RAS-GTP levels and total RAS protein by 44% and 25%, respectively in HtTA cells; however, the suppression was not observed in truncated HRASLS2 variants. In conclusion, the HRASLS2 protein suppressed growth and RAS activities of cancer cells, and the C-terminal hydrophobic domain appeared to be indispensable for both activities.
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PMID:Cloning and functional characterization of the HRASLS2 gene. 1816 83

Nowadays, there is increasing evidence that some pathogenic bacteria can contribute to specific stages of cancer development. The concept that bacterial infection could be involved in carcinogenesis acquired a widespread interest with the discovery that H. pylori is able to establish chronic infections in the stomach and that this infection is associated with an increased risk of gastric adenocarcinoma and mucosa associated lymphoid tissue lymphoma. Chronic infections triggered by bacteria can facilitate tumor initiation or progression since, during the course of infection, normal cell functions can come under the control of pathogen factors that directly manipulate the host regulatory pathways and the inflammatory reactions.Renowned publications have recently corroborated the molecular mechanisms that link bacterial infections, inflammation and cancer, indicating certain strains of Escherichia coli as a risk factor for patients with colon cancer. E. coli is a normal inhabitant of the human intestine that becomes highly pathogenic following the acquisition of virulence factors, including a protein toxin named cytotoxic necrotizing factor 1 (CNF1). This toxin permanently activates the small GTP-binding proteins belonging to the Rho family, thus promoting a prominent polymerization of the actin cytoskeleton as well as a number of cellular responses, including changes in protein expression and functional modification of the cell physiology. CNF1 is receiving an increasing attention as a putative factor involved in transformation because of its ability to: (i) induce COX2 expression, an immediate-early gene over-expressed in some type of cancers; (ii) induce a long-lasting activation of the transcription factor NF-kB, a largely accepted marker of tumor cells; (iii) protect epithelial cells from apoptosis; (iv) ensue the release of pro-inflammatory cytokines in epithelial and endothelial cells; and (v) promote cellular motility. As cancer may arise through dysfunction of the same regulatory systems, it seems likely that CNF1-producing E. coli infections can contribute to tumor development.This review focuses on the aspects of CNF1 activity linked to cell transformation with the aim of contributing to the identification of a possible carcinogenic agent from the microbial world.
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PMID:The Rho-activating CNF1 toxin from pathogenic E. coli: a risk factor for human cancer development? 1833 18

Several studies indicate that cancer-associated fibroblasts play a critical role in cancer cell invasion and metastasis, the hallmarks of malignancy. To better understand the mechanisms underlying such effects, we established a heterotypic model of human fibroblasts (primary colon fibroblasts and immortalized human dermal fibroblasts) in co-culture with human colon cancer cells (HCT-8/E11), using three-dimensional collagen type-I and Matrigel matrices. We report that TGF-beta is the unique and dominant factor to provide pro-invasive signals to HCT-8/E11 colon cancer cells from TGF-beta-treated human fibroblasts in three-dimensional collagen type I and Matrigel matrices. These effects are not mimicked or reversed by EGF or bFGF, and are associated with the TGF-beta-mediated induction of myofibroblast differentiation and functional markers, such as alpha-SMA, the haptotactic matrix molecule TNC, collagen type 1 maturation enzyme P4H, serine protease FAP, and myofibroblast contractility. Accordingly, TGF-beta induced a strong activation of RhoA and stress fiber formation in fibroblasts, with no impact on Rac1-GTP levels. In contrast, EGF down-regulated Rho-GTP levels in fibroblasts, giving permissive signals for Rac1 activation, fibroblast polarization, and invasion. Taken together, our data imply that TGF-beta and EGF exert invasive growth-promoting actions in human colon tumors through a differential and cumulative impact on the stromal and cancer cell compartments. Our data predict that inhibitors directed at this reciprocal molecular and cellular crosstalk will have therapeutic applications for targeting the invasive growth of human primary tumors and their metastatic spread.
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PMID:Differential impact of TGF-beta and EGF on fibroblast differentiation and invasion reciprocally promotes colon cancer cell invasion. 1842 81

Rho/ROCK signaling and caveolin-1 (Cav1) are implicated in tumor cell migration and metastasis; however, the underlying molecular mechanisms remain poorly defined. Cav1 was found here to be an independent predictor of decreased survival in breast and rectal cancer and significantly associated with the presence of distant metastasis for colon cancer patients. Rho/ROCK signaling promotes tumor cell migration by regulating focal adhesion (FA) dynamics through tyrosine (Y14) phosphorylation of Cav1. Phosphorylated Cav1 is localized to protrusive domains of tumor cells and Cav1 tyrosine phosphorylation is dependent on Src kinase and Rho/ROCK signaling. Increased levels of phosphorylated Cav1 were associated with elevated GTP-RhoA levels in metastatic tumor cells of various tissue origins. Stable expression and knockdown studies of Cav1 in tumor cells showed that phosphorylated Cav1 expression stimulates Rho activation, stabilizes FAK association with FAs, and promotes cell migration and invasion in a ROCK-dependent and Src-dependent manner. Tyrosine-phosphorylated Cav1, therefore, functions as an effector of Rho/ROCK signaling in the regulation of FA turnover and, thereby, tumor cell migration and invasion. These studies define a feedback loop between Rho/ROCK, Src, and phosphorylated Cav1 in tumor cell protrusions, identifying a novel function for Cav1 in tumor metastasis that may contribute to the poor prognosis of some Cav1-expressing tumors.
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PMID:Phosphorylated caveolin-1 regulates Rho/ROCK-dependent focal adhesion dynamics and tumor cell migration and invasion. 1892 92

In human colon cancer cells, cisplatin-induced apoptosis involves the Fas death receptor pathway independent of Fas ligand. The present study explores the role of ezrin and actin cytoskeleton in relation with Fas receptor in this cell death pathway. In response to cisplatin treatment, a rapid and transient actin reorganisation is observed at the cell membrane by fluorescence microscopy after Phalloidin-FITC staining. This event is dependent on the membrane fluidification studied by electron paramagnetic resonance and necessary for apoptosis induction. Moreover, early after the onset of cisplatin treatment, ezrin co-localised with Fas at the cell membrane was visualised by membrane microscopy and was redistributed with Fas, FADD and procaspase-8 into membrane lipid rafts as shown on Western blots. In fact, cisplatin exposure results in an early small GTPase RhoA activation demonstrated by RhoA-GTP pull down, Rho kinase (ROCK)-dependent ezrin phosphorylation and actin microfilaments remodelling. Pretreatment with latrunculin A, an inhibitor of actin polymerisation, or specific extinction of ezrin or ROCK by RNA interference prevents both cisplatin-induced actin reorganisation and apoptosis. Interestingly, specific extinction of Fas receptor by RNA interference abrogates cisplatin-induced ROCK-dependent ezrin phosphorylation, actin reorganisation and apoptosis suggesting that Fas is a key regulator of cisplatin-induced actin remodelling and is indispensable for apoptosis. Thus, these findings show for the first time that phosphorylation of ezrin by ROCK via Fas receptor is involved in the early steps of cisplatin-induced apoptosis.
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PMID:Cisplatin-induced apoptosis involves a Fas-ROCK-ezrin-dependent actin remodelling in human colon cancer cells. 2020 22


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