Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0009402 (colorectal cancer)
 53,228 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations in the tumor suppressor gene APC invariably lead to the development of colorectal cancer. The vast majority of these mutations are nonsense or frameshifts resulting in nonfunctional, truncated APC protein products. Eleven cyclin-dependent kinase (CDK) consensus phosphorylation sites have been identified in the frequently deleted carboxyl-terminal region of APC; loss of these phosphorylation sites by mutation could therefore compromise the ability of APC to inhibit cell growth. This report demonstrates that immunoprecipitates of full-length, but not truncated, APC protein include a mitosis-specific kinase activity in vivo. Biochemical and Western analysis of these immunoprecipitates confirms the presence of the CDK p34(cdc2). We also show that APC is a substrate for recombinant human p34(cdc2)-cyclin B1. Modification of APC by p34(cdc2) implicates phosphorylation as a mechanism for regulating APC function via a link to the cell cycle.
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PMID:Phosphorylation of the tumor suppressor adenomatous polyposis coli (APC) by the cyclin-dependent kinase p34. 926 94

14-3-3Sigma is a member of a family of proteins that regulate cellular activity by binding and sequestering phosphorylated proteins. It has been suggested that 14-3-3sigma promotes pre-mitotic cell-cycle arrest following DNA damage, and that its expression can be controlled by the p53 tumour suppressor gene. Here we describe an improved approach to the generation of human somatic-cell knockouts, which we have used to generate human colorectal cancer cells in which both 14-3-3sigma alleles are inactivated. After DNA damage, these cells initially arrested in the G2 phase of the cell cycle, but, unlike cells containing 14-3-3sigma, the 14-3-3sigma-/- cells were unable to maintain cell-cycle arrest. The 14-3-3sigma-/- cells died ('mitotic catastrophe') as they entered mitosis. This process was associated with a failure of the 14-3-3sigma-deficient cells to sequester the proteins (cyclin B1 and cdc2) that initiate mitosis and prevent them from entering the nucleus. These results may indicate a mechanism for maintaining the G2 checkpoint and preventing mitotic death.
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PMID:14-3-3Sigma is required to prevent mitotic catastrophe after DNA damage. 1052 15

We investigated the effect of an acidic environment on the radiation-induced G2/M arrest and apoptosis using RKO.C human colorectal cancer cells expressing wild-type p53 and RC10.1 cells, a subline of RKO.C cells deficient in p53 as well as p53+/+ MEFs and p53-/- MEFs (mouse embryonic fibroblasts). The cells were irradiated with 4 Gy or 12 Gy of gamma-rays in pH 7.5 medium or pH 6.6 medium. p53 accentuated the progression of cells from radiation-induced G2/M arrest to apoptosis and the pH 6.6 environment suppressed the progression of cells through G2/M-phase to apoptosis after irradiation. Further analysis indicated that the radiation-induced G2/M arrest was due mainly to G2 arrest in both pH 7.5 and pH 6.6. Therefore, it was concluded that p53 enhances, and an acidic environment suppresses, the exit of cells from radiation-induced G2 arrest by altering cyclin B1-Cdc2 kinase activity.
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PMID:Cell cycle progression and apoptosis after irradiation in an acidic environment. 1091 47

In this study, we demonstrate that apoptosis and G2/M cell cycle arrest were easily induced by treatment with the oral-antifungal agent, griseofulvin (GF). The mechanisms of GF-induced G2/M arrest were characterized as (a) induction of abnormal mitotic spindle formation, (b) elevation of cyclin B1/cdc2 kinase activity and (c) down-regulation of myt-1 protein expression. On the other hand, caspase 3 activation, Bcl-2 hyperphosphorylation and inhibition of the normal function of Bcl-2 associated with Bax were demonstrated to be the mechanisms of GF-induced apoptosis. DNA fragmentation and flow cytometry analyses demonstrated that combined treatment of GF with the cancer chemotherapeutic agent, nocodazole (ND), strongly potentiates the apoptotic effect and arrest of the G2/M cell cycle in 5 types of human cancer cells, but not in normal human keratinocytes (#76 KhGH). The combined treatment of GF and ND triggered the polymerization of purified tubulin in HT 29 but not in #76 KhGH cells. To further confirm these observations, the therapeutic efficacy was further examined in vivo by treating athymic mice bearing COLO 205 tumor xenografts, with GF (50 mg/kg), ND (5 mg/kg) or GF + ND. Combined treatment of GF and ND significantly enhanced the effect of ND, and led to cessation of tumor growth. These results suggest that chemotherapeutic agents (such as ND) administered in the presence of GF might provide a novel therapy for colorectal cancer.
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PMID:Griseofulvin potentiates antitumorigenesis effects of nocodazole through induction of apoptosis and G2/M cell cycle arrest in human colorectal cancer cells. 1116 65

5-Fluorouracil (5-FU) is one of the most widely used anticancer agents for advanced colorectal carcinoma, but its response rate is only 15%. The "pharmacokinetic modulating chemotherapy" (PMC) regimen that we have advocated has proved to be highly effective in treating colorectal carcinoma. PMC consists of a continuous i.v. infusion of 5-FU over 24 h for 1day a week at 600 mg/m2/day, and an oral dose of uracil-tegafur (UFT), a 5-FU derivative, at 400 mg/day for 5-7 days per week, repeated every week for more than 6 months. Assays of 5-FU in 23 patients receiving this treatment showed serum concentrations ranging from 88 to 1,323 ng/ml. We then analyzed the effects of clinically relevant concentrations of 5-FU found in colorectal cancer patients treated with the PMC regimen on the growth of three human colorectal adenocarcinoma cell lines, SW480 and COLO320DM (mutant p53) and HCT116 (wild-type p53). Exposure of these three cell lines to 5-FU resulted in growth inhibition in a dose-dependent manner. Exposure to 100 ng/ml of 5-FU in SW480 and COLO320DM caused G1 arrest after 24 h and G2 arrest after 72-144 h, and only a minority of the cell population showed apoptotic features, which indicated that most of the cells were killed through mitotic catastrophe, nonapoptotic cell death. On the contrary, exposure to 1000 ng/ml of 5-FU in SW480 and COLO320DM resulted in G1-S-phase arrest and the induction of apoptosis throughout the experimental period. Nuclear cyclin B1 expression was markedly induced with exposure to 100 ng/ml of 5-FU in SW480 and COLO320DM; and expression of 14-3-3sigma protein, a cell cycle inhibitor in the GG phase, was induced in SW480. ICT116 responded to lower concentrations of 5-FU more rapidly: G2 arrest was seen after 24-72 h of exposure to 10 ng/ml of 5-FU, and G,1rrest was seen after 12-24 h of exposure to 100 ng/ml. These results show that 5-FU acts via two different pathways, depending on dose: (a) G,1S-phase cell cycle arrest and apoptosis at 1,000 ng/ml in SW480 and COLO320DM, and 100 ng/ml in HCT116; and (b) G2-M-phase cell cycle arrest and mitotic catastrophe at 100 ng/ll in SW480 and COLO320DM, and 10 ng/ml in HCT116. These results suggest that the efficacy of our PMC regimen is based on targeting at least two different phases of the cell cycle. In our clinical trial, we showed efficacy independent of p53 status, ascertained by cell kinetic analysis in vitro, which may lead to a novel concept of schedule-oriented biochemical modulation of this drug.
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PMID:Dual antitumor effects of 5-fluorouracil on the cell cycle in colorectal carcinoma cells: a novel target mechanism concept for pharmacokinetic modulating chemotherapy. 1122 29

DNA mismatch repair (MMR) is an efficient system for the detection and repair of mismatched and unpaired bases in DNA. Deficiencies in MMR are commonly found in both hereditary and sporadic colorectal cancers, as well as in cancers of other tissues. Because fluorinated thymidine analogues (which through their actions might generate lesions recognizable by MMR) are widely used in the treatment of colorectal cancer, we investigated the role of MMR in cellular responses to 5-fluorouracil and 5-fluoro-2'-deoxyuridine (FdUrd). Human MLH1(-) and MMR-deficient HCT116 colon cancer cells were 18-fold more resistant to 7.5 microM 5-fluorouracil (continuous treatment) and 17-fold more resistant to 7.5 microM FdUrd in clonogenic survival assays compared with genetically matched, MLH1(+) and MMR-proficient HCT116 3-6 cells. Likewise, murine MLH1(-) and MMR-deficient CT-5 cells were 3-fold more resistant to a 2-h pulse of 10 microM FdUrd than their MLH1(+) and MMR-proficient ME-10 counterparts. Decreased cytotoxicity in MMR-deficient cells after treatment with various methylating agents and other base analogues has been well reported and is believed to reflect a tolerance to DNA damage. Synchronized HCT116 3-6 cells treated with a low dose of FdUrd had a 2-fold greater G(2) cell cycle arrest compared with MMR-deficient HCT116 cells, and asynchronous ME-10 cells demonstrated a 4-fold greater G(2) arrest after FdUrd treatment compared with CT-5 cells. Enhanced G(2) arrest in MMR-proficient cells in response to other agents has been reported and is believed to allow time for DNA repair. G(2) cell cycle arrest as determined by propidium iodide staining was not a result of mitotic arrest, but rather a true G(2) arrest, as indicated by elevated cyclin B1 levels and a lack of staining with mitotic protein monoclonal antibody 2. Additionally, p53 and GADD45 levels were induced in FdUrd-treated HCT116 3-6 cells. DNA double-strand break (DSB) formation was 2-fold higher in MMR-proficient HCT116 3-6 cells after FdUrd treatment, as determined by pulsed-field gel electrophoresis. The formation of DSBs was not the result of enhanced apoptosis in MMR-proficient cells. FdUrd-mediated cytotoxicity was caused by DNA-directed and not RNA-directed effects, because administration of excess thymidine (and not uridine) prevented cytotoxicity, cell cycle arrest, and DSB formation. hMLH1-dependent responses to fluoropyrimidine treatment, which may involve the action of p53 and the formation of DSBs, clearly have clinical relevance for the use of this class of drugs in the treatment of tumors with MMR deficiencies.
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PMID:Role of the hMLH1 DNA mismatch repair protein in fluoropyrimidine-mediated cell death and cell cycle responses. 1143 59

The regular use of various nonsteroidal anti-inflammatory drugs (NSAIDs) was shown to decrease the incidence of colorectal cancer. This effect is thought to be caused predominantly by inhibition of cyclooxygenase-2 (COX-2) and, subsequently, prostaglandin synthesis. However, recent studies have suggested that COX-independent pathways may contribute considerably to these antiproliferative effects. To evaluate the involvement of COX-dependent and COX-independent mechanisms further, we assessed the effects of celecoxib (selective COX-2 inhibitor) and SC560 (selective COX-1 inhibitor) on cell survival, cell cycle distribution, and apoptosis in three colon cancer cell lines, which differ in their expression of COX-2. Both drugs induced a G0/G1 phase block and reduced cell survival independent of whether or not the cells expressed COX-2. Celecoxib was more potent than SC560. The G0/G1 block caused by celecoxib could be attributed to a decreased expression of cyclin A, cyclin B1, and cyclin-dependent kinase-1 and an increased expression of the cell cycle inhibitory proteins p21Waf1 and p27Kip1. In addition, celecoxib, but not SC560, induced apoptosis, which was also independent of the COX-2 expression of the cells. In vivo, celecoxib as well as SC560 reduced the proliferation of HCT-15 (COX-2 deficient) colon cancer xenografts in nude mice, but both substances had no significant effect on HT-29 tumors, which express COX-2 constitutively. Thus, our in vitro and in vivo data indicate that the antitumor effects of celecoxib probably are mediated through COX-2 independent mechanisms and are not restricted to COX-2 over-expressing tumors.
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PMID:COX-2 independent induction of cell cycle arrest and apoptosis in colon cancer cells by the selective COX-2 inhibitor celecoxib. 1160 77

We investigated the effects of an acidic environment on the G2/M-phase arrest, apoptosis, clonogenic death, and changes in cyclin B1-CDC2 kinase activity caused by a 4-Gy irradiation in RKO.C human colorectal cancer cells in vitro. The time to reach peak G2/M-phase arrest after irradiation was delayed in pH 6.6 medium compared to that in pH 7.5 medium. Furthermore, the radiation-induced G2/M-phase arrest decayed more slowly in pH 6.6 medium than in pH 7.5 medium. Finally, there was less radiation-induced apoptosis and clonogenic cell death in pH 6.6 medium than in pH 7.5 medium. It appeared that the prolongation of G2-phase arrest after irradiation in the acidic environment allowed for greater repair of radiation-induced DNA damage, thereby decreasing the radiation-induced cell death. The prolongation of G2-phase arrest after irradiation in the acidic pH environment appeared to be related at least in part to a prolongation of the phosphorylation of CDC2, which inhibited cyclin B1-CDC2 kinase activity.
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PMID:Influence of environmental pH on G2-phase arrest caused by ionizing radiation. 1249 71

An immunohistochemical method for assessing cell-cycle phase distribution in colorectal resection specimens would enable phase data to be incorporated into diagnostic algorithms for the estimation of prognosis and response to adjuvant chemotherapy in colorectal cancer. In contrast to flow cytometry, an immunohistochemical method would also allow the phase distribution to be examined within morphologically heterogeneous regions of neoplasms. Paraffin sections of normal colon (n = 25), colonic adenoma (n = 15), and colonic adenocarcinoma (n = 30) were analysed by immunohistochemistry using antibodies against markers of cell-cycle entry, Mcm-2 and Ki67, and putative markers of the cell-cycle phase, cyclins D1 and E (putative markers of G1 phase), cyclin A (S phase), cytoplasmic cyclin B1 (G2 phase), and phosphohistone H3 (M phase). The phase specificity of each marker was assessed by examining the degree of co-expression of adjacent phase markers using double-antibody fluorescence confocal microscopy and by comparison with flow cytometric analysis performed on adjacent tissue sections. The S-phase specificity of detectable cyclin A was also assessed in combination with in situ DNA replication using fluorescence confocal microscopy. All cells expressing phase markers co-expressed Mcm-2. Adjacent phase markers were not significantly co-expressed, confirming the relative specificity of these markers in tissue sections of colon. Cell-cycle phase distribution, calculated by immunohistochemistry, compared well with phase analyses obtained by flow cytometry. No cells expressed cyclin A in the absence of active DNA replication. The S-phase labelling index, as defined by detectable cyclin A expression, showed a positive correlation with the Mcm-2 labelling index and increased in the progression from normal colon to adenocarcinoma. In conclusion, a combination of these cell-cycle phase markers can be used to calculate the distribution of cells throughout each phase of the cell cycle in colorectal tissue sections. Detectable cyclin A can be used as a surrogate marker of S phase and may be of value in predicting prognosis and response to adjuvant therapy.
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PMID:A novel immunohistochemical method to estimate cell-cycle phase distribution in archival tissue: implications for the prediction of outcome in colorectal cancer. 1451 35

In many kinds of cancers, 14-3-3sigma, one of the cell cycle negative regulator, is inactivated by hypermethylation of the gene. In colorectal cancers, this study revealed that the hypermethylation of the 14-3-3sigma gene was an uncommon event and 14-3-3sigma expression was kept even in established colorectal cancer cell lines. Immunohistochemical study using surgical materials showed the expression of 14-3-3sigma was localized at the deep peripheral area of the tumor, so-called invasion front. According to the results of Ki-67 and cyclin B1 immunohistochemistry, 14-3-3sigma-positive cases maintained higher proliferative activity compared to 14-3-3sigma-negative cases at IF. However, a significant correlation between 14-3-3sigma expression and proliferative activity in CRC cells remains to be unsolved.
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PMID:Inactivation of 14-3-3sigma by hypermethylation is a rare event in colorectal cancers and its expression may correlate with cell cycle maintenance at the invasion front. 1507 34


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