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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent evidence from molecular biology studies of the cell cycle machinery suggests that, apart from oncogenes and tumor suppressor genes, the genes encoding the key cell cycle regulatory proteins could serve as additional targets for oncogenic mutations involved in the multistep process of carcinogenesis. In an attempt to identify such potential cancer-associated aberrations of the cell cycle regulators, the expression of cdc2 and cdk2 kinases, as well as cyclins A, B1 and D1, was analyzed by immunoblotting in a panel of more than 40 human cancer cell lines derived from 17 different tumor types. The expression of cdc2, cdk2, cyclin B1 and cyclin A polypeptides was detectable in all lines examined, and moderate variation in protein level does not provide evidence for any obvious abnormalities in the cancer cell lines studied. The application of a series of novel monoclonal antibodies (Mab) to human cdc2 revealed the existence of an intriguing protein, designated p37, immunologically and structurally related to cdc2, which is strongly and selectively expressed in about 50% of the cancer cell lines. In contrast to cyclin A, which has also been implicated in tumorigenesis, we found pronounced variation in abundance of the cyclin D1 protein. Our data suggest that dysregulation of cyclin D1 (a candidate bcl-1, PRAD1 oncogene) can be involved in the pathogenesis of some additional tumor types (e.g., sarcomas and neuroblastomas) besides those reported for amplification and/or mRNA overexpression of this oncogene.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Molecular pathology of the cell cycle in human cancer cells. 831 19

Apigenin is a plant flavonoid which has been shown to significantly inhibit UV-induced mouse skin tumorigenesis when applied topically, and may represent an alternative sunscreen agent in humans. We have investigated the molecular mechanism(s) by which apigenin inhibits skin tumorigenesis. Initial studies examined the effects of apigenin on the cell cycle. DNA flow cytometric analysis indicated that culturing cells for 24 h in medium containing apigenin induced a G2/M arrest in two mouse skin derived cell lines, C50 and 308, as well as in human HL-60 cells. The G2/M arrest was fully reversible after an additional 24 h in medium without apigenin. We investigated the effects of apigenin on cyclin B1 and p34cdc2, since cyclin B1/p34cdc2 complexes regulate G2/M progression. Western blot and immune complex kinase assays using whole cell lysates from 308 and C50 cells treated for 24 h with 0-70 microM doses of apigenin demonstrated that apigenin treatment did not change the steady-state level of p34cdc2 protein, but did inhibit p34cdc2 H1 kinase activity in 308 cells. Western blot analysis showed that apigenin treatment of C50 cells and 308 cells inhibited the accumulation of cyclin B1 protein in a dose-dependent manner. The apigenin levels detected in cultured keratinocytes were relevant to those detected in epidermal cells of Sencar mice treated with tumor inhibitory doses of apigenin. In conclusion, we present evidence that apigenin induces a reversible G2/M arrest in cultured keratinocytes, the mechanism of which is in part due to inhibition of the mitotic kinase activity of p34cd2, and perturbation of cyclin B1 levels.
Carcinogenesis 1996 Nov
PMID:The chemopreventive flavonoid apigenin induces G2/M arrest in keratinocytes. 896 50

The mechanisms underlying peroxisome proliferator-induced hepatocarcinogenesis are unclear but are mediated by the peroxisome proliferator-activated receptor alpha (PPARalpha). To determine the role of PPARalpha in the mechanisms of hepatocarcinogenesis, the effect of Wy-14,643 on expression patterns of acyl CoA oxidase (ACO) and proteins involved in cell proliferation in the PPARalpha-null mouse were evaluated. ACO, CDK-1, CDK-2, CDK-4, PCNA and c-myc proteins were significantly increased in wild-type mice fed Wy-14,643 for 5 weeks or 11 months, as compared with controls. This effect was not observed in Wy-14,643-treated PPARalpha-null mice. Expression patterns of cyclin B1, cyclin D, cyclin E and p53 were not different in any of the groups. mRNAs encoding CDK-1, CDK-4, cyclin D1 and c-myc were also increased in wild-type mice fed Wy-14,643 but not in PPARalpha-null mice. These results indicate that the increase in CDK-1, CDK-4 and c-myc may be caused by an increase in transcription that is mediated directly or indirectly by PPARalpha. Thus PPARalpha-dependent alterations in cell cycle regulatory proteins induced by peroxisome proliferators are likely to contribute to the hepatocarcinogenicity of peroxisome proliferators.
Carcinogenesis 1998 Nov
PMID:Role of peroxisome proliferator-activated receptor alpha in altered cell cycle regulation in mouse liver. 985 14

The development of a malignant tumor involves the progressive acquisition of mutations and epigenetic abnormalities in multiple genes that have highly diverse functions. Some of these genes code for pathways of signal transduction that mediate the action of growth factors. The enzyme protein kinase C plays an important role in these events and in the process of tumor promotion. Therefore, we examined the effects of three inhibitors of protein kinase C, CGP 41251, RO 31-8220, and calphostin C, on human glioblastoma cells. These compounds inhibited growth and induced apoptosis; these activities were associated with a decrease in the level of CDC2 and cyclin B1/CDC2-associated kinase activity. This may explain why the treated cells accumulated in G2-M. In a separate series of studies, we examined abnormalities in cell cycle control genes in human cancer. We have found that cyclin D1 is frequently overexpressed in a variety of human cancers. Mechanistic studies indicate that cyclin D1 can play a critical role in carcinogenesis because: overexpression enhances cell transformation and tumorigenesis; introduction of an antisense cyclin D1 cDNA into either human esophageal or colon cancer cells reverts their malignant phenotype; and overexpression of cyclin D1 can enhance the amplification of other genes. The latter finding suggests that cyclin D1 can enhance genomic instability and, thereby, the process of tumor progression. Therefore, inhibitors of the function of cyclin D1 may be useful in both cancer chemoprevention and therapy. We obtained evidence for the existence of homeostatic feedback loops between cyclins D1 or E and the cell cycle inhibitory protein p27Kip1. On the basis of these and other findings, we hypothesize that, because of their disordered circuitry, cancer cells suffer from "gene addiction" and "gene hypersensitivity," disorders that might be exploited in both cancer prevention and therapy.
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PMID:Disorders in cell circuitry associated with multistage carcinogenesis: exploitable targets for cancer prevention and therapy. 1006 76

In vitro two-stage transformation, an important method for the screening of carcinogens, is a valuable approach for the mechanistic study of multi-stage carcinogenesis. However, very little is known about the molecular and cellular mechanisms, particularly in terms of cell cycle control during in vitro two-stage transformation. We improved the in vitro two-stage transformation method using N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) as an initiator and cadmium as a promoter, and reconfirmed the promotional effect of cadmium (Fang et al., 2001a). To determine the alterations of cell cycle control in the MNNG-induced initiation stage during transformation, we examined the effects of MNNG on Balb/3T3 A31 cell growth, and determined the alterations of the protein and/or mRNA levels of cyclins B1, D1, E, and G, PCNA, GADD45, p27, and wild-type p53. After 4 hour treatment of MNNG, populations of G2/M phase distribution and apoptotic fraction and the cyclin G mRNA level increased, while the cyclin B1 mRNA level decreased in a concentration-dependent manner. Wild-type p53, p27, and GADD45 protein levels also increased as a function of MNNG concentrations. However, cyclin D1, cyclin E, and PCNA expressions remained unchanged. During the initiation stage, PCNA protein expression decreased on the first day after MNNG-treatment, then increased gradually during the following 6 days, and further increased on the first day after cadmium treatment. Although wild-type p53 and p27 protein expressions also showed temporary retardation on the first day after MNNG-treatment, the expressions increased gradually during the following 6 days, but decreased rapidly by the cadmium treatment. These results indicated that during the initiation stage, MNNG induced G2/M arrest and apoptosis with increased expressions of wild-type p53, p27, and GADD45 proteins; and down-regulated mRNA level of cyclin B1 and up-regulated mRNA level of cyclin G. In addition, although a few of the G2/M-arrested cells proliferated gradually, most cells continued to be suppressed and inactivated by the over-expressions of wild-type p53 and p27 until the cadmium treatment.
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PMID:Cell cycle was disturbed in the MNNG-induced initiation stage during in vitro two-stage transformation of Balb/3T3 cells. 1151 27

Lovastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, induces growth arrest in a variety of cancer cell lines. Its mechanism of action, however, has not been completely elucidated. E2F-1 is thought to act as an oncogene and a tumour suppressor, with its action probably dependent upon the cellular context. We have shown in this study that transcriptional regulation and proteasomal degradation of E2F-1 are critical regulatory events in lovastatin-induced cell death. Accompanying this is a reduction in the E2F-1-regulated expression of cell cycle genes such as c-myc, cyclin D1, cyclin A and cyclin B1. Cell cycle analysis demonstrated that the accumulation of apoptotic cells was preceded by a progressive decrease in the S-phase cell population in response to lovastatin. Although expression of E2F-1 was reduced in three prostate cancer cell lines-PC-3, LNCaP and DU-145-the p21 and p27 protein levels were not increased in all the cell lines treated, suggesting that increase in p21 and p27 protein expression per se is not responsible for lovastatin-mediated down-regulation of E2F-1. The subsequent apoptotic death of these cells in the presence of lovastatin can be prevented by forced ectopic expression of E2F-1. Taken together, these facts imply that E2F-1 is the target of an HMG-CoA inhibitor and critical cell death mediator in prostate cancer cells.
Carcinogenesis 2001 Oct
PMID:Lovastatin-induced E2F-1 modulation and its effect on prostate cancer cell death. 1157 16

The short-chain fatty acid (SCFA) butyrate is produced via anaerobic bacterial fermentation within the colon and is thought to be protective in regard to colon carcinogenesis. Although butyrate (C4) is considered the most potent of the SCFA, a variety of other SCFA also exist in the colonic lumen. Butyrate is thought to exert its cellular effects through the induction of histone hyperacetylation. We sought to determine the effects of a variety of the SCFA on colon carcinoma cell growth, differentiation and apoptosis. HT-29 or HCT-116 (wild-type and p21-deleted) cells were treated with physiologically relevant concentrations of various SCFA, and histone acetylation state was assayed by acid-urea-triton-X gel electrophoresis and immunoblotting. Growth and apoptotic effects were studied by flow cytometry, and differentiation effects were assessed using transient transfections and Northern blotting. Propionate (C3) and valerate (C5) caused growth arrest and differentiation in human colon carcinoma cells. The magnitude of their effects was associated with a lesser degree of histone hyperacetylation compared with butyrate. Acetate (C2) and caproate (C6), in contrast, did not cause histone hyperacetylation and also had no appreciable effects on cell growth or differentiation. SCFA-induced transactivation of the differentiation marker gene, intestinal alkaline phosphatase (IAP), was blocked by histone deacetylase (HDAC), further supporting the critical link between SCFA and histones. Butyrate also significantly increased apoptosis, whereas the other SCFA studied did not. The growth arrest induced by the SCFA was characterized by an increase in the expression of the p21 cell-cycle inhibitor and down-regulation of cyclin B1 (CB1). In p21-deleted HCT-116 colon cancer cells, the SCFA did not alter the rate of proliferation. These data suggest that the antiproliferative, apoptotic and differentiating properties of the various SCFA are linked to the degree of induced histone hyperacetylation. Furthermore, SCFA-mediated growth arrest in colon carcinoma cells requires the p21 gene.
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PMID:The effects of short-chain fatty acids on human colon cancer cell phenotype are associated with histone hyperacetylation. 1198 30

Medulloblastoma (MB) is a primitive neuroectodermal tumor (PNET) of the central nervous system (CNS) and the most common malignant primary brain tumor in children. Currently, poor risk and recurrent MB patients are treated with cytotoxic chemotherapy alone or in combination with surgery and irradiation. In order to improve on therapeutic outcome and reduce toxicity of current treatment strategies, new and novel therapeutic agents are needed for MB patients. To that purpose, we have examined the effect of 2-methoxyestradiol (2-ME), an endogenous non-toxic estrogenic metabolite on the growth of three medulloblastoma cell lines (DAOY, D341 and D283); and two high-grade anaplastic astrocytoma/glioblastoma cell lines, U-87MG and T-98-G. We present evidence to show that 2-ME preferentially inhibits the growth of medulloblastoma cells significantly by blocking cell cycle progression predominantly in G(2)/M phase. 2-ME treatment results in phosphorylation of cdc25C without any significant alterations in the expression of cyclin B1 or p34cdc2. In addition, we observed a decrease in the levels of 14-3-3 proteins following treatment with 2-ME. Furthermore, 2-ME-mediated growth inhibition is accompanied by induction of apoptosis as evidenced by morphological alterations and DNA fragmentation analysis. Of interest is the finding that 2-ME induced apoptosis is not mediated through alterations in the expression of p53 or Bax and that transcriptional activity of NF kappa B and DNA binding activity is reduced indicating that 2-ME disrupts the NF kappa B signaling pathway. These results suggest that 2-ME may prove to be a useful therapeutic agent in the treatment of PNET brain tumors such as medulloblastoma. In addition, as 2-ME inhibits growth predominantly through G(2)/M block, it may enhance the effectiveness of radiation therapy.
Carcinogenesis 2003 Feb
PMID:2-Methoxyestradiol interferes with NF kappa B transcriptional activity in primitive neuroectodermal brain tumors: implications for management. 1258 69

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a compound found in cooked meat, is a mammary gland carcinogen in rats. Comparative genomic hybridization of PhIP-induced rat mammary gland carcinomas revealed loss in the centromeric region of 2q, a region known to carry the mammary carcinoma susceptibility 1 (Mcs1) gene and several other genes relevant to carcinogenesis. Allelic imbalance, specifically microsatellite instability and loss of heterozygosity, was examined in mammary gland carcinomas induced by PhIP in Sprague-Dawley (SD)xWistar Furth F1 hybrid rats. In a polymerase chain reaction (PCR)-based assay with 34 microsatellite markers coinciding to 2q11-2q16, nine markers revealed allelic imbalance. The frequency of imbalance in the tumors varied from 10 to 100% depending on the specific marker. However, none of the markers coinciding with the Mcs1 gene locus showed allelic imbalance, suggesting that alterations at this locus were not associated with PhIP-induced rat mammary gland cancer. The expression of several genes physically mapped to 2q11-2q16 and potentially involved in carcinogenesis including Ccnb (cyclin B1), Ccnh (cyclin H), Rasa (Ras GAP), Rasgrf2, Pi3kr1 (p85alpha), and Il6st (gp130) was also examined by quantitative real-time PCR and immunohistochemistry (IHC) across a large bank of PhIP-induced SD rat mammary gland carcinomas. By quantitative real-time PCR, the mRNA expression of Rasa, Pi3kr1, Ccnh, and Il6st in carcinomas was, respectively, 22-, 20-, three- and threefold higher in carcinomas than in control mammary gland tissues (P<0.05, Student's t-test). A statistically sixfold lower expression of Rasgrf2 was detected in carcinomas whereas no significant change in Ccnb1 expression was observed. The findings from quantitative real-time PCR were confirmed by IHC for each gene. In addition, the proliferation index in mammary gland carcinomas as assessed by PCNA was found to correlate with the overexpression of Cyclin H by IHC analysis (P<0.05, Spearman Rank Order Correlation). The findings from the current study implicate molecular alterations in the proximal region of 2q in PhIP-induced rat mammary gland carcinomas.
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PMID:Allelic imbalance and altered expression of genes in chromosome 2q11-2q16 from rat mammary gland carcinomas induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine. 1260 53

Ubiquitin-mediated proteolysis of cell cycle regulators is a major element of the cell cycle control. The anaphase-promoting complex (APC/C) is a large multisubunit ubiquitin-protein ligase required for the ubiquitination and degradation of G1 and mitotic checkpoint regulators. APC/C-dependent proteolysis regulates cyclin levels in G1, and triggers the separation of sister chromatids at the metaphase-anaphase transition and the destruction of mitotic cyclins at the end of mitosis. Furthermore, it was recently shown that APC/C regulates the degradation of crucial regulators of signal transduction pathways. We report here gene alterations in several components of this complex in human colon cancer cells, including APC6/CDC16 and APC8/CDC23 which are known to be key function elements. The experimental expression of a truncation mutant of APC8/CDC23 subunit (CDC23DeltaTPR) leads to abnormal levels of APC/C targets such as cyclin B1 and disturbs the cell cycle progression of colon epithelial cells through mitosis. Overall, these data support the hypothesis of a deleterious role of these mutations during colorectal carcinogenesis.
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PMID:Alterations of anaphase-promoting complex genes in human colon cancer cells. 1262 11


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