Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Survivin, a member of the apoptosis inhibitor family, shows increased expression in human cancers of various origins. It has been demonstrated that survivin inhibits apoptosis via caspase inhibition and promotes mitosis via aurora-B kinase activation. We recently reported that survivin enhances the expression of human telomerase reverse transcriptase (hTERT), a major determinant of telomerase activity in colon cancer cells. Survivin up-regulates hTERT expression by promoting the expression of specificity protein-1 (Sp1)- and c-Myc-mediated gene transcription via enhancing the phosphorylation of these transcriptional factors. However, the mechanism by which survivin regulates the phosphorylation of Sp1 and c-Myc is not well defined. In the present study, we hypothesized that survivin promotes the phosphorylation of Sp1 and c-Myc by activating aurora-B kinase. Inhibition of this enzyme by introducing small inhibitory RNA attenuated the phosphorylation of Sp1 and c-Myc and resulted in the abolition of the survivin effect on hTERT expression. In addition, blocking survivin phosphorylation at a threonine residue by inhibiting cyclin-dependent kinase 1 caused the dissociation of aurora-B kinase from survivin and attenuated the up-regulation of hTERT expression by survivin. Taken together, these results suggest that the interaction between survivin and aurora-B kinase may be essential for survivin to increase hTERT expression.
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PMID:Interaction between survivin and aurora-B kinase plays an important role in survivin-mediated up-regulation of human telomerase reverse transcriptase expression. 1928 63

Selenium (Se), a dietary trace metal essential for human health, is incorporated into selenoproteins as selenocysteine. Selenoprotein P (SePP), the major plasma selenoprotein, has both transport and antioxidant functions. In humans, it exists in plasma as two isoforms of approximately 50 and 60 kDa. This study investigated the effect of polymorphisms in the SEPP-1 gene, Se supplementation, and disease status on the proportions of SePP plasma isoforms. SePP was isolated from plasma from healthy volunteers, before and after a 6-week supplementation with 100 microg sodium selenite, and from colon cancer patients and controls. SePP isoform distribution was analysed by Western blot. In healthy volunteers, the relative abundance of each isoform depended on two SEPP-1 polymorphisms: rs3877899, predicted to cause an Ala-to-Thr amino acid change at position 234, and rs7579, located in the 3'-untranslated region of SEPP-1 mRNA. The difference between genotypes disappeared after Se supplementation. A genotype-dependent reduction was seen in the proportion of the 60-kDa isoform in patients with colorectal cancer compared with controls. We conclude that functional polymorphisms in the SEPP-1 gene influence the proportion of SePP isoforms in plasma. An elevated proportion of the 60-kDa isoform of SePP may increase selenoprotein synthesis and reduce colorectal cancer risk.
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PMID:Relative abundance of selenoprotein P isoforms in human plasma depends on genotype, se intake, and cancer status. 1945 53

Butyrate is an inhibitor of histone deacetylase (HDAC) and has been extensively evaluated as a chemoprevention agent for colon cancer. We recently showed that mutations in the adenomatous polyposis coli (APC) gene confer resistance to HDAC inhibitor-induced apoptosis in colon cancers. Here, we show that APC mutation rendered colon cancer cells resistant to butyrate-induced apoptosis due to the failure of butyrate to down-regulate survivin in these cells. Another cancer-preventive agent, 3,3'-diindolylmethane (DIM), was identified to be able to down-regulate survivin in colon cancers expressing mutant APC. DIM inhibited survivin mRNA expression and promoted survivin protein degradation through inhibition of p34(cdc2)-cyclin B1-mediated survivin Thr(34) phosphorylation. Pretreatment with DIM enhanced butyrate-induced apoptosis in colon cancer cells expressing mutant APC. DIM/butyrate combination treatment induced the expression of proapoptotic Bax and Bak proteins, triggered Bax dimerization/activation, and caused release of cytochrome c and Smac proteins from mitochondria. Whereas overexpression of survivin blocked DIM/butyrate-induced apoptosis, knocking down of survivin by small interfering RNA increased butyrate-induced apoptosis in colon cancer cells. We further showed that DIM was able to down-regulate survivin and enhance the effects of butyrate in apoptosis induction and prevention of familial adenomatous polyposis in APC(min/+) mice. Thus, the combination of DIM and butyrate is potentially an effective strategy for the prevention of colon cancer.
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PMID:3,3'-diindolylmethane enhances the efficacy of butyrate in colon cancer prevention through down-regulation of survivin. 1947 Jul 89

PHLPP1 belongs to a novel family of Ser/Thr protein phosphatases that serve as tumor suppressors by negatively regulating Akt signaling. Our recent studies have demonstrated that loss of PHLPP expression occurs at high frequency in colorectal cancer. In this study, we identified PHLPP1 as a proteolytic target of a beta-TrCP-containing Skp-Cullin 1-F-box protein (SCF) complex (SCF(beta-TrCP)) E3 ubiquitin ligase in a phosphorylation-dependent manner. Overexpression of wild-type but not DeltaF-box mutant beta-TrCP leads to decreased expression and increased ubiquitination of PHLPP1, whereas knockdown of endogenous beta-TrCP has the opposite effect. In addition, we show that the beta-TrCP-mediated degradation requires phosphorylation of PHLPP1 by casein kinase I and glycogen synthase kinase 3beta (GSK-3beta), and activation of the phosphatidylinositol 3-kinase/Akt pathway suppresses the degradation of PHLPP1 by inhibiting the GSK-3beta activity. Furthermore, expression of a degradation-deficient PHLPP1 mutant in colon cancer cells results in a more effective dephosphorylation of Akt and inhibition of cell growth. Taken together, our findings demonstrate a key role for beta-TrCP in controlling the level of PHLPP1, and activation of Akt negatively regulates this degradation process.
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PMID:beta-TrCP-mediated ubiquitination and degradation of PHLPP1 are negatively regulated by Akt. 1979 85

Mutations in protein kinases can drive cancer through alterations of the kinase activity or by uncoupling kinase activity from regulation. Changes to protein expression in Aurora A, a mitotic Ser/Thr kinase, are associated with the development of several human cancers, but the effects of somatic cancer-associated mutations have not been determined. In this study we show that Aurora A kinase activity is altered in different ways in three somatic cancer-associated mutations located within the catalytic domain; Aurora A(V174M) shows constitutively increased kinase activity, Aurora A(S155R) activity is decreased primarily due to misregulation, and Aurora A(S361*) activity is ablated due to loss of structural integrity. These alterations suggest vastly different mechanisms for the role of these three mutations in human cancer. We have further characterized the Aurora A(S155R) mutant protein, found that its reduced cellular activity and mislocalization are due to loss of interaction with TPX2, and deciphered the structural basis of the disruption at 2.5 A resolution. Previous studies have shown that disruption of the Aurora A/TPX2 interaction results in defective spindles that generate chromosomal abnormalities. In a panel of 40 samples from microsatellite instability-positive colon cancer patients, we found one example in which the tumor contained only Aurora A(S155R), whereas the normal tissue contained only wild-type Aurora A. We propose that the S155R mutation is an example of a somatic mutation associated with this tumor type, albeit at modest frequency, that could promote aneuploidy through the loss of regulated interactions between Aurora A and its protein partners.
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PMID:A cancer-associated aurora A mutant is mislocalized and misregulated due to loss of interaction with TPX2. 1980 54

Tn-antigens are generally masked by covalently linked carbohydrates but are exposed in most primary and metastatic epithelial malignant tumors, providing sensitive markers for detection of carcinoma. Here, therapeutic potentials of tumor-associated carbohydrate antigen-specific antibodies were investigated. MLS128, an anti-Tn monoclonal antibody, binds to a carbohydrate epitope consisting of three consecutive Tn-antigens (GalNAcalpha-Ser/Thr). MLS128 treatment significantly inhibited colon and breast cancer cell growth. MLS128 bound to 110-210 kDa glycoproteins on the cell surface. MLS128 treatment caused down-regulation of insulin-like growth factor-I receptor and epidermal growth factor receptor in LS180 colon cancer cells, suggesting that MLS128-inhibited cancer cell growth is in part mediated by down-regulation of growth factor receptors. This study provides the first insights into the potential use of this particular type of anti-Tn antigen antibodies as a cancer therapeutic.
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PMID:Inhibition of cancer cell growth by anti-Tn monoclonal antibody MLS128. 2010 42

We reported previously that protein kinase C-alpha (PKC-alpha) negatively regulates Wnt/beta-catenin signalling pathway. The current study explores the role of PKC-alpha in the regulation of proliferation of colon cancer cells, which contain aberrant up-regulation of intracellular beta-catenin. In colon tissue and cells, an inverse correlation was observed between the expression levels of PKC-alpha and intracellular beta-catenin. Activation of PKC-alpha inhibited beta-catenin response transcription by down-regulation of intracellular beta-catenin and induced phosphorylation of the N-terminal serine and threonine residues (Ser33/Ser37/Thr41) of beta-catenin, marking it for proteasomal degradation, in colon cancer cells. Pharmacological inhibition or depletion of PKC-alpha-abrogated PKC-alpha-mediated beta-catenin down-regulation and phosphorylation in colon cancer cells. Notably, the Ser45 residue of beta-catenin was essential for PKC-alpha-induced beta-catenin down-regulation in colon cancer cells. Moreover, PKC-alpha activation repressed the expression of cyclin D1 and c-myc, which are known beta-catenin target genes, and thus inhibited the growth of colon cancer cells. These findings suggest that PKC-alpha negatively regulates colon cancer cell proliferation viabeta-catenin phosphorylation/down-regulation and may facilitate the development of new strategies to treatment of colon cancer.
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PMID:Stimulation of protein kinase C-alpha suppresses colon cancer cell proliferation by down-regulation of beta-catenin. 2014 13

Protein kinase C (PKC) isoenzymes are expressed and activated in a cell type-specific manner, and play an essential role in tissue-specific signal transduction. The presence of butyrate at millimolar concentrations in the colon raises the question of whether it affects the expression of PKC isoenzymes in the different cell types of the colonic epithelium. We investigated the protein expression levels of PKCgamma, Thr(514)-phosphorylated PKCgamma (pPKCgamma-Thr(514)), and their subcellular distribution as affected by butyrate in a set of colon cancer cell lines. Thr(514)-phosphorylation of de novo synthesized PKCgamma is the first step in priming of the inactive PKCgamma before its release into the cytoplasm. For immunoblot analysis, we employed three antibodies, one against an unmodified sequence, mapping within 50 amino acids at its C-terminus, a second against pPKCgamma-Thr(514), and a third against pPKCgamma-pan-Thr(514). The antibody against an unmodified C-terminal peptide epitope did not recognize pPKCgamma-Thr(514), suggesting that phosphorylation at this site interferes with the binding of the antibody to the C-terminus. Marked butyrate-induced upregulation of PKCgamma occurred in HT29 cells (model for colonocyte stem cells) and HT29-derived cell lines. However, in Caco2 and IEC-18 cells (models for differentiated intestinal epithelial cells), PKCgamma was insensitive to upregulation, and present exclusively as pPKCgamma-Thr(514). Lovo and SW480 expressed higher levels of PKCgamma. In HT29 cells, butyrate-induced upregulation of the non-phosphorylated PKCgamma was observed in both the membrane and the cytosolic fraction. In Caco2 cells, the Thr(514)-phosphorylated form was present at high levels in both fractions. The presence of unphosphorylated PKCgamma in HT29 cells, and its complete absence in Caco2 cells demonstrates a cell type-dependent differential coupling of Thr(514)-phosphorylation with de novo synthesis of PKCgamma in colon cancer cells.
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PMID:Protein kinase Cgamma in colon cancer cells: expression, Thr514 phosphorylation and sensitivity to butyrate-mediated upregulation as related to the degree of differentiation. 2018 13

The serine/threonine protein kinase LKB1 is a tumor suppressor gene mutated in Peutz-Jeghers syndrome patients. The mutations are found also in several types of sporadic cancer. Although LKB1 is implicated in suppression of cell growth and metastasis, the detailed mechanisms have not yet been elucidated. In this study, we investigated the effect of LKB1 on cell motility, whose acquisition occurs in early metastasis. The knockdown of LKB1 enhanced cell migration and PAK1 activity in human colon cancer HCT116 cells, whereas forced expression of LKB1 in Lkb1-null mouse embryonic fibroblasts suppressed PAK1 activity and PAK1-mediated cell migration simultaneously. Notably, LKB1 directly phosphorylated PAK1 at Thr(109) in the p21-binding domain in vitro. The phosphomimetic T109E mutant showed significantly lower protein kinase activity than wild-type PAK1, suggesting that the phosphorylation at Thr(109) by LKB1 was responsible for suppression of PAK1. Consistently, the nonphosphorylatable T109A mutant was resistant to suppression by LKB1. Furthermore, we found that PAK1 was activated in the hepatocellular carcinomas and the precancerous liver lesions of Lkb1(+/-) mice. Taken together, these results suggest that PAK1 is a direct downstream target of LKB1 and plays an essential role in LKB1-induced suppression of cell migration.
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PMID:LKB1 suppresses p21-activated kinase-1 (PAK1) by phosphorylation of Thr109 in the p21-binding domain. 2040 May 10

The p21-activated kinase (PAK) family of serine/threonine kinases plays an important role in cell proliferation, survival and motility, as well as in cell transformation and tumor progression. PAK1 promotes transformation through facilitating the ERK/MAPK pathway and enhances cell migration and survival by stimulating AKT. PAK1 expression increases with the progression of colorectal cancer (CRC). In this study, we have investigated the importance of PAK1 in the biology of colon cancer cells. Reduction of PAK1 expression decreased the activities of ERK and AKT leading to decreased cell proliferation, migration/invasion, and survival. Dual inhibition of ERK and AKT suppressed these cellular processes to levels comparable to those achieved by reduction of PAK1 expression, whereas inactivation of either the ERK or AKT pathway alone partially inhibited cell migration/invasion and survival and had no effect on proliferation. We conclude that PAK1 stimulates colon cancer cell proliferation, migration/invasion, and survival via ERK- and AKT-dependent pathways. These findings establish the central importance of PAK1 in CRC signal transduction and clarify the mechanism by which PAK1 regulates CRC growth and migration. Instead of simultaneously inhibiting both ERK and AKT, the PAK1 convergence point could be an alternative target for CRC therapy.
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PMID:P21-activated kinase 1 stimulates colon cancer cell growth and migration/invasion via ERK- and AKT-dependent pathways. 2059 63


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