Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Transition from an epithelioid (E) to a round (R) morphotype, in the human colon cancer cell line HCT-8, is associated with loss or truncation of alphaE-catenin and acquisition of invasiveness in organ culture. In E clones, like in parental HCT-8 cells, one allele of the alphaE-catenin gene (CTNNA1) is mutated. HCT-8 cells have also a 'Microsatelite Instability-High' (MSI-H) phenotype presumably due to a mutated hMSH6 gene. Fusion of E type cells doubles the wild type CTNNA1 alleles and prevents the loss of alphaE-catenin. Introduction of an extra chromosome 2, carrying a wild type hMSH6 gene, restores post-replicative mismatch repair and also prevents the frequent inactivation of the remaining wild type CTNNA1 allele.
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PMID:hMSH6 deficiency and inactivation of the alphaE-catenin invasion-suppressor gene in HCT-8 colon cancer cells. 1091 11

Some studies have shown an inverse relationship between microsatellite instability in colon cancer and mutations in p53 and K-ras, whereas others have not. We therefore evaluated these features in a population-based sample of 496 individuals with colon cancer. Microsatellite instability was determined by a panel of 10 tetranucleotide repeats, the Bethesda consensus panel of mono- and dinucleotide repeats, and coding mononucleotide repeats in transforming growth factor-beta receptor type II, hMSH3, BAX, hMSH6, and insulin-like growth factor receptor type II. Mutations in codons 12 and 13 in K-ras were evaluated by sequencing. p53 overexpression (as detected by immunohistochemistry) was used as an indicator of p53 mutation; this was evaluated in 275 of the tumors. K-ras mutations were present in 33.2% of tumors, p53 overexpression in 51.5%, and microsatellite instability (as determined by the Bethesda consensus panel) in 12.5%. K-ras mutations were significantly less common in unstable tumors than stable tumors (11.8% versus 36.9%, P: < 0.001). p53 overexpression was significantly less common in unstable tumors than stable tumors (20.0% versus 55.7%, P: < 0.001). These inverse relationships between microsatellite instability and ras gene mutations and p53 overexpression were shown to be independent of tumor site in logistic regression analyses. All other measures of instability also showed statistically significant inverse relationships independent of tumor site with alterations in ras and p53, and instability results determined by the panel of 10 tetranucleotide repeats were highly significantly related to those determined by the Bethesda consensus panel. Coding mononucleotide repeat mutations were significantly more common in unstable tumors than stable tumors (85.7% versus 1.0%, P: < 0.001). We conclude that there is an inverse relationship between microsatellite instability and mutations in p53 and K-ras, and that the molecular profile of colon cancers with microsatellite instability is characterized by relatively infrequent mutations in K-ras and p53 and relatively frequent mutations in coding mononucleotide repeats.
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PMID:Inverse relationship between microsatellite instability and K-ras and p53 gene alterations in colon cancer. 1129 May 69

The ability of O(6)-benzylguanine (BG) to inactivate alkyltransferase (AGT) to potentiate the antitumor efficacy of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) is being tested in clinical trials. As of now, there are no examples of acquired resistance to BG+BCNU in the clinical setting. However, we hypothesized that genetically unstable tumors might develop resistance to the combination after repeated drug-exposures to achieve therapeutic efficacy. To evaluate this possibility, we treated three colon cancer cell lines that are either proficient in mismatch repair (MMR) [SW480 (MMR wild type)] or deficient in MMR [HCT116 (hMLH1 mutant) and HCT15 (hMSH6 mutant)] with three cycles of BG+BCNU. After drug-treatments, HCT116 and HCT15 were completely resistant to BG-potentiated cytotoxicity of BCNU. In these two cell lines, the acquired BG resistance resulted from two de novo and different mutations at amino acid 165 in AGT: 165-lysine (K) to glutamic acid (E) (K165E in HCT116), and 165-lysine to asparagine (N) (K165N in HCT15). Both K165-mutated AGTs had markedly decreased enzymatic activity because of unstable AGT protein but were remarkably resistant to BG inactivation. FISH analysis showed that only one copy of MGMT gene exists in HCT116 cells, and the status of promoter methylation of MGMT in HCT15 showed that one allele of the MGMT promoter has an aberrant methylation. Thus, the MGMT gene expressing AGT either from one copy (HCT116) or from unmethylated allele (HCT15) was mutated because of the exposure to BG+BCNU in these two MMR-deficient cell lines. Conversely, MMR-proficient SW480 cells, treated with three cycles of BG+BCNU, maintained wt AGT and the sensitivity to BG-potentiated BCNU-cytotoxicity. To confirm that K165-mutated AGT proteins were responsible for resistance to BG+BCNU, we transfected K165E and K165N MGMT cDNAs into Chinese hampster ovary (CHO) cells. Transfected CHO cells had low AGT activity but increased IC(50) for either BCNU or temozolomide (TMZ), compared with parental CHO cells. BG did not potentiate the cytotoxicity of these two alkylating agents at concentrations up to 200 microM; in contrast, BG, at 25 microM, sensitized CHO-AGT (transfected with wt MGMT cDNA) cells to BCNU or TMZ-cytotoxicity by 3-4 fold. These results suggest that K165 AGT mutants arising in MMR-deficient tumor cells after treatment with chemotherapeutic agents are both resistant to BG-inactivation and are active in the repair of alkylated DNA adducts.
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PMID:Chemotherapy-induced O(6)-benzylguanine-resistant alkyltransferase mutations in mismatch-deficient colon cancer. 1203 16

The first exon of the human androgen receptor (AR) contains a translated CAG (poly-glutamine) repeat. The repeat length is polymorphic in the normal population ranging from 8 to 35 repeats. Expansions to over 40 repeats lead to spinal bulbar muscular atrophy (SBMA), a late onset neurodegenerative disease. The repeat is located between the two parts of a bipartite amino-terminal transactivation function and the repeat length, also within in the normal range, is inversely correlated to the transactivation power of the receptor. P160 type co-activators bind more strongly to shorter repeats. A correlation between AR CAG repeat length and total risk, age at diagnosis, recurrence after surgery and aggressive growth has been reported for tumors of classical androgen target tissues. In the prostate, where androgens exert a mitogenic effect, the cancer risk increases with decreasing AR-CAG repeat length. In contrast, in the breast, where the hormone probably acts as anti-mitogen, a higher risk and earlier onset of breast cancer has been reported for carriers of BRCA1 mutations who also have long CAG repeats in the receptor gene. Somatic alterations during carcinogenesis appear to be frequent in endometrial and in colon cancer. In the endometrium the AR CAG repeat prevalently undergoes expansions consistent with the putative protective function of androgens in this tissue. Frequent repeat reductions during colon carcinogenesis would be consistent with a mitogenic effect of androgens. Analysis of AR protein expression by Western blot reveals expression of the AR in healthy and neoplastic colon tissues. Normal mucosa of the colon expresses both AR-isoforms of 110 and 87 kDa, while the tumor samples have lost the expression of the 110-kDa isoform. The 87-kDa isoform is devoid of the amino-terminal portion of the receptor molecule that also contains the poly-glutamine tract. The temporal and causal relation between isoform switch and somatic repeat reductions during colon carcinogenesis is as yet unclear, but the two events could both enhance p160 mediated androgen signaling. The recent finding that smad3 interacts with the AR in a way similar to p160 links the AR to TGFbeta signaling. Interruption of this signaling pathway is a frequent event in colon carcinogenesis.
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PMID:The androgen receptor CAG repeat: a modifier of carcinogenesis? 1216 Oct 10

Base excision repair (BER) is a fundamental cellular process used to reduce the cytotoxicity of alkylating agent chemotherapy. Heretofore, no therapeutic agents have targeted this DNA repair pathway. Methoxyamine (MX), which binds abasic sites, acting as an inhibitor of BER, was evaluated in combination with the methylating agent temozolomide (TMZ). Three human colon cancer cell lines were used, SW480 cells, which are wild-type for mismatch repair genes and have mutated p53, HCT116 cells, which are mutant in hMLH1 and wild-type for p53, and HCT15 cells, which are mutant in hMSH6 and mutant in p53 as well. Nude mice carrying these tumors received TMZ alone or in combination with MX or O(6)-benzylguanine (BG), an inhibitor of O(6)-alkylguanine DNA-alkyltransferase, daily i.p. for 5 consecutive days. At the highest tolerable dose of TMZ (120 mg/kg), a tumor growth delay of approximately 9.3 +/- 1.2 days was noted in SW480. Addition of BG resulted in a tumor growth delay of 25 +/- 2.4 days accompanied by significant weight loss (23%) and severe myelosuppression. In contrast, SW480 tumor-bearing mice treated with MX + TMZ had cessation of tumor growth for 50 +/- 13 days and very slow regrowth, yielding tumor growth delays of >70 +/- 14 days (P < 0.002) without additive systemic toxicity. HCT116 and HCT15 xenografts were completely resistant to treatment with TMZ alone or in combination with BG. However, treatment with MX + TMZ induced significant tumor growth delays (20 +/- 1.4 days in HCT116 and 14 +/- 3.1 days in HCT15 xenografts, P < 0.05). These studies demonstrate that a significant enhancement of the antitumor effect of TMZ by MX was observed in human colon cancer xenografts with mismatch repair proficiency and deficiency. DNA BER may be a useful pharmacological target through which tumor cells can be sensitized to alkylating therapeutic agents.
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PMID:Base excision repair as a therapeutic target in colon cancer. 1223 45

Familial colorectal cancer (CRC) is noted in about 15% of incident CRC cases, and at times is hallmarked by an age at diagnosis less than 50 years. Familial adenomatous polyposis (FAP) and hereditary non-polyposis colon cancer (HNPCC) account for about 40% of familial cases. Thus, the majority of familial and early-onset CRC remain genetically elusive. Similarly, the majority of familial and early onset endometrial cancer (EC), the most prevalent extracolonic tumor in HNPCC, are genetically undefined. An attractive candidate is the hMSH6 gene. Israeli patients with early onset (age under 50 years) (n = 44) and familial nonsyndromic (n = 23) CRC, and women with familial clustering of EC or CRC (n = 12), and those diagnosed with EC at, or under, the age of 50 years (n = 5) were genotyped for germ-line mutations within the hMSH6 gene. Exon-specific PCR was followed by denaturing gradient gel electrophoresis (DGGE) analysis, complemented by DNA sequencing of abnormally migrating fragments. No patients displayed a truncating mutation, and 1 CRC patient harbored a novel missense mutation (V878A). In addition, 6 previously described polymorphisms were detected. In conclusion, mutations in the hMSH6 gene occur uncommonly in Israeli patients with familial and early-onset CRC and EC.
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PMID:Mutational analysis of the hMSH6 gene in familial and early-onset colorectal and endometrial cancer in Israeli patients. 1253 58

Previous studies from our laboratory indicated that expression of the MLH1 DNA mismatch repair (MMR) gene was necessary to restore cytotoxicity and an efficient G(2) arrest in HCT116 human colon cancer cells, as well as Mlh1(-/-) murine embryonic fibroblasts, after treatment with 5-fluoro-2'-deoxyuridine (FdUrd). Here, we show that an identical phenomenon occurred when expression of MSH2, the other major MMR gene, was restored in HEC59 human endometrial carcinoma cells or was present in adenovirus E1A-immortalized Msh2(+/+) (compared with isogenic Msh2(-/-)) murine embryonic stem cells. Because MMR status had little effect on cellular responses (i.e. G(2) arrest and lethality) to the thymidylate synthase inhibitor, Tomudex, and a greater level of [(3)H]FdUrd incorporation into DNA was found in MMR-deficient cells, we concluded that the differential FdUrd cytotoxicity between MMR-competent and MMR-deficient cells was mediated at the level of DNA incorporation. Analyses of ATPase activation suggested that the hMSH2-hMSH6 heterodimer only recognized FdUrd moieties (as the base 5-fluorouracil (FU) in DNA) when mispaired with guanine, but not paired with adenine. Furthermore, analyses of incorporated FdUrd using methyl-CpG-binding domain 4 glycosylase indicated that there was more misincorporated FU:Gua in the DNA of MMR-deficient HCT116 cells. Our data provide the first demonstration that MMR specifically detects FU:Gua (in the first round of DNA replication), signaling a sustained G(2) arrest and lethality.
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PMID:DNA mismatch repair-dependent response to fluoropyrimidine-generated damage. 1561 Oct 52

HNPCC (hereditary non-polyposis colon cancer) is an autosomal-dominant disorder characterized by early-onset CRC (colorectal cancer). HNPCC is most often associated with mutations in the MMR (mismatch repair) genes hMLH1, hMSH2, hMSH6 or hPMS2. The mutator phenotype of a defective MMR system is MSI (microsatellite instability), which also occurs in approx. 15-25% of sporadic CRC cases, where it is associated with the hypermethylation of the promoter region of hMLH1. Dietary factors, including excessive alcohol consumption, ingestion of red meat and low folate intake, may increase the risk of MSI high tumour development. In contrast, aspirin may suppress MSI in MMR-deficient CRC cell lines. Butyrate, a short-chain-fatty-acid end product of carbohydrate fermentation in the colon, shares a number of anti-neoplastic properties with aspirin, including inhibiting proliferation and inducing apoptosis of CRC cells. Recent in vitro studies suggest that physiological concentrations of butyrate (0.5-2 mM) may have more potent anti-neoplastic effects in CRC cell lines deficient in MMR, but mechanisms for such a differential response remain to be established.
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PMID:DNA mismatch repair status may influence anti-neoplastic effects of butyrate. 1604 86

Germline mutations in DNA mismatch repair (DNA-MMR) genes, mainly hMlh1 and hMsh2, underlie Hereditary Non-Polyposis Colorectal Cancer (HNPCC). Germline hMSH6 gene mutations have been reported in a small subset of HNPCC families. In the present study, ethnically diverse individuals with HNPCC and HNPCC-like features were genotyped for hMsh6 germline mutations using exon-specific PCR, DGGE, and DNA sequencing. The study encompassed 92 individuals representing 88 unrelated families who were previously analyzed for Msh2 and Mlh1 mutations: Jewish Ashkenazim (n = 44), non-Ashkenazim (n = 27), Israeli Moslem-Arab (n = 15), Druze (n=3), and Cypriot non-Jews (n = 3). Of the study population, 71 had colon cancer (CRC), mean age at diagnosis was 50.9+/-13.2 years (range 16-73 years), 5 had endometrial cancer (two with concurrent CRC), (mean 43.6+/-3.26 years, range 38-45 years), and unaffected individuals (n = 18) were first degree relatives within HNPCC families and were genotyped at a mean age of 48.3+/-11.7 years (range 30-69 years). Of the 92 individuals analyzed, none showed a truncating hMsh6 mutation, and 6 (6.6%) harbored one of three germline missense mutations: a previously reported one (V878A), and two novel mutations (V509A, S227I). The pathogenic significance of these three missense mutations is yet unclear. In addition, 5 polymorphisms were detected, 2 of which were novel. We conclude that the rate of pathogenic hMsh6 mutations in HNPCC families of Jewish and Mediterranean origin is low, and that mutations in other genes probably account for the phenotype in these families.
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PMID:Mutational analysis of hMsh6 in Israeli HNPCC and HNPCC-like families. 1634 5

Phorbol ester was known to activate protein kinase C (PKC) and exert numerous cellular effects, including proliferation, apoptosis, and oncogenic transformation. How phorbol ester stimulates both apoptosis and tumor promotion is not clear. Here DNA mismatch repair (MMR)-proficient human colon cancer cells (DLD-1+Ch2; hMSH6+) treated with 12-O-tetradecanoylphorbol-13-acetate (TPA) undergo rapid cell death, which is significantly abolished by staurosporine (PKC inhibitor) or antioxidant, compared with the paired MMR-deficient (DLD-1; hMSH6-) cells. Induction of reactive oxygen species (ROS) by TPA is shown to be one of downstream effectors required, but not sufficient, for cell killing as it is also observed in DLD-1 cells. Strikingly, DLD-1+Ch2 cells selected for resistance to TPA are found to lose the expression of hMSH6. Treatment of TPA-resistant DLD-1+Ch2 cells with 5-aza-2'-deoxycytidine, not only restores hMSH6 expression but also resensitizes TPA-resistant cells to TPA, suggesting that expression of hMSH6 is transcriptionally silenced by cytosine methylation confirmed directly by bisulfite sequencing. Knockdown hMSH6 or hPMS2 with siRNA in DLD-1+Ch2 cells resulted in more resistant to TPA-induced cell killing, further suggesting that MMR proteins involve in TPA or ROS-induced cell killing. Results suggest that deficiency in MMR could promote tumorigenesis by inhibiting apoptotic responses to ROS-mediated DNA damages as ROS are continuously produced as a byproduct of normal metabolism.
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PMID:DNA mismatch repair as an effector for promoting phorbol ester-induced apoptotic DNA damage and cell killing: implications in tumor promotion. 1672 13


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