UMLS:C0596263 - FACTA Search

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

The inhibitor of apoptosis protein survivin is selectively expressed in tumor cells. The tobacco component nicotine increases the transcription of the survivin gene in non-small cell lung cancer cells. However, the role of survivin expression induced by tobacco component is not clear during lung carcinogenesis. We investigated the effects of the tobacco components nicotine and its related carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) on survivin expression in normal human bronchial epithelial (NHBE) cells and examined the role of survivin in the malignant transformation of normal human bronchial epithelial (HBE) cells induced by these components. We found that survivin messenger RNA (mRNA) expression was detected in 41% (7 of 17) of bronchial brush specimens from heavy smokers. Nicotine and NNK increased survivin mRNA and protein expression levels in primary cultured NHBE cells and immortalized HBE cells. Bronchial epithelium in mice administered NNK also showed increased staining for survivin. Nicotine and NNK stimulated the Akt-mammalian target of rapamycin (mTOR) pathway in NHBE cells, leading to increased de novo synthesis of survivin protein. Induced survivin expression increased the survival potential of the cells, which was blocked by transfection with survivin-specific small interfering RNA (siRNA). siRNA-induced down-regulation of survivin expression also suppressed the tumorigenic potential of premalignant and malignant HBE cells exposed to the tobacco components. These findings suggest that NNK and nicotine induce survivin protein synthesis in NHBE cells by activating the Akt-mTOR pathway and thus blockade of the pathway effectively inhibits the tobacco-induced malignant transformation of HBE cells.
Carcinogenesis 2008 Aug
PMID:Survivin expression in normal human bronchial epithelial cells: an early and critical step in tumorigenesis induced by tobacco exposure. 1863 26

The deregulation of apoptosis is characteristic of human carcinogenesis. Survivin, an inhibitor of apoptosis, p53 and p16, two tumour suppressor proteins involved in cell cycle control, play a central role in apoptosis. The aim of this study was to investigate, in primary cutaneous melanoma from 68 patients, the expression of survivin with respect to p53 or p16; the association of these proteins, alone or in combination with clinicopathological features; and, most importantly, to elucidate the role of these markers in predicting survival. The level of survivin expression was significantly higher in the p53 positive group of melanomas compared with the p53 negative one, suggesting a cooperative effect in favouring the progression of melanoma, while no correlation was found between survivin and p16. Moreover, the altered expression of nuclear survivin, p53 and p16 were all associated with poor survival, as demonstrated by univariate analysis. However, these biomarkers have been shown to have superior predictive value when studied in combination (P<0.0001) rather than alone, while the risk of mortality grew progressively with increasing the number of altered biomarkers. These data suggest that the assessment of the combined marker status and number of altered markers in patients with melanoma provides important additional prognostic information that may help in patient selection for adjuvant therapies.
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PMID:Combinations of apoptosis and cell-cycle control biomarkers predict the outcome of human melanoma. 1863 86

Farnesol is a catabolite within the isoprenoid/cholesterol pathway that has exhibited significant antitumor activity. Farnesol was recently identified as a quorum-sensing molecule produced by the fungal pathogen Candida albicans. In this study, we hypothesize that synthetic and Candida-produced farnesol can induce apoptosis in vitro in oral squamous cell carcinoma (OSCC) lines. Cell proliferation, apoptosis, mitochondrial degradation, and survivin and caspase expressions were examined. In addition, global protein expression profiles were analyzed using proteomic analysis. Results demonstrated significant decrease in proliferation and increase in apoptosis in cells exposed to farnesol and C. albicans culture media. Concurrently, protein expression analysis demonstrated a significant decrease in survivin and an increase in cleaved-caspase expression, whereas fluorescent microscopy revealed the presence of active caspases with mitochondrial degradation in exposed cells. A total of 36 differentially expressed proteins were identified by proteomic analysis. Among the 26 up-regulated proteins were those involved in the inhibition of carcinogenesis, proliferation suppression, and aging. Most notable among the 10 down-regulated proteins were those involved in the inhibition of apoptosis and proteins overexpressed in epithelial carcinomas. This study demonstrates that farnesol significantly inhibits the proliferation of OSCCs and promotes apoptosis in vitro through both the intrinsic and extrinsic apoptotic signaling pathways. In addition, we report for the first time the ability of Candida-produced farnesol to induce a similar apoptotic response through the same pathways. The capability of farnesol to trigger apoptosis in cancer cells makes it a potential tool for studying tumor progression and an attractive candidate as a therapeutic agent.
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PMID:Farnesol, a fungal quorum-sensing molecule triggers apoptosis in human oral squamous carcinoma cells. 1871 96

There is much evidence that dietary Ca(2+) loading reduces colon cell proliferation and carcinogenesis in humans and rodents, but during carcinogenesis it becomes ineffective or even tumor-promoting. We are beginning to see how Ca(2+) balances the continuous massive cell production in colon crypts by driving the terminal differentiation and eventually the apoptosis of the cells mainly on the mucosal surface, and how this Ca(2+) control is lost during colon carcinogenesis. The rapid proliferation of the transit-amplifying (TA) progeny of the colon stem cells is driven by the so-called "Wnt" signaling mechanism, which involves the stimulation of proliferogenic genes such as those for c-Myc and cyclin D1 and the silencing of the gene for the cell cycle-stopping p21(Cip1/WAF1) protein by nuclear beta-catenin*Tcf-4 complexes. TA cells avoid mitotic damage and premature apoptosis by expressing the protein survivin. It appears that TA cell cycling stops and terminal differentiation starts when the cells reach a higher level in the crypt where there is enough lumenal Ca(2+) to stimulate the expression and activation of CaSRs (Ca(2+)-sensing receptors), the signals from which stimulate the expression of E-cadherin. Along with this, the APC (adenomatous polyposis coli) protein appears and some of it enters the nucleus. There it makes the TA cells susceptible to the eventual apoptotic balancing by stopping survivin expression and the beta-catenin*Tcf-4 complex from driving further cell cycling by releasing beta-catenin from the nucleus, and delivering it to cytoplasmic APC*axin*GSK-3beta complexes for ultimate proteasomal destruction. Cytoplasmic beta-catenin is then prevented from returning to the nucleus by either being intercepted and destroyed by APC*axin*GSK-3beta complexes or locked by the emerging E-cadherin into membrane adherens junctions which tie the cell into the sheet of proliferatively shut-down cells with APC-dependent cytoskeletons moving to the mouth of the crypt and onto the flat mucosal surface. A common first step in sporadic colon carcinogenesis is the loss of functional APC which disorients upwardly directed migration and causes the retention of nuclear beta-catenin and proliferogenic beta-catenin*Tcf-4 complexes as well as genomic instability. Eventually the balance between cell proliferation and terminal differentiation and death is radically tipped in favour of proliferation by the appearance of apoptosis-resistant, survivin-expressing clones of Ca(2+)-insensitive cells which are locked into the proliferative, mutation-prone mode because of CaSR-disabling gene mutations which prevent the stimulation of E-cadherin expression and terminal differentiation.
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PMID:Calcium, calcium-sensing receptor and colon cancer. 1872 75

Survivin is a crucial node molecule involved in apoptosis, cell division and drug discovery. Up-regulation of survivin in the tissues of oral submucous fibrosis (OSF) and oral squamous cell carcinoma (OSCC) originated from OSF has already been demonstrated. Survivin Thr34 phosphorylation is involved in the inhibition of apoptosis and cell division. To determine the potential involvement of survivin Thr34 phosphorylation in carcinogenesis of OSF, 40 OSFs, 42 OSCCs originated from OSF and 10 normal tissues from surgical specimens were studied. Immunohistochemistry showed that the positive staining rate of the survivin phosphorylation on Thr34 in OSCC originated from OSF group was significantly higher than that in OSF group (P<0.01), and none in the normal oral mucosa specimens. Survivin phosphorylation on Thr34 is predominantly located in the nucleus, which account for its function in apoptosis at cell division. Western blotting analysis showed increasing expression of survivin Thr34 phosphorylation, cyclin B1 and p34cdc2 in carcinogenesis of OSF. Furthermore, p34cdc2-cyclin B1 kinase was confirmed to phosphorylate survivin on Thr34 in carcinogenesis of OSF by immunoprecipitation and immunoblot. These results suggest that the phosphorylation of survivin on Thr34 critically regulate survivin and plays an important role during the malignant transformation of OSF, which will provide an indication to early diagnosis and therapy in carcinogenesis of OSF.
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PMID:The phosphorylation of survivin Thr34 by p34cdc2 in carcinogenesis of oral submucous fibrosis. 1894 5

Picroliv, an iridoid glycoside derived from the plant Picrorhiza kurroa, is used traditionally to treat fever, asthma, hepatitis, and other inflammatory conditions. However, the exact mechanism of its therapeutic action is still unknown. Because nuclear factor-kappaB (NF-kappaB) activation plays a major role in inflammation and carcinogenesis, we postulated that picroliv must interfere with this pathway by inhibiting the activation of NF-kappaB-mediated signal cascade. Electrophoretic mobility shift assay showed that pretreatment with picroliv abrogated tumor necrosis factor (TNF)-induced activation of NF-kappaB. The glycoside also inhibited NF-kappaB activated by carcinogenic and inflammatory agents, such as cigarette smoke condensate, phorbol 12-myristate 13-acetate, okadaic acid, hydrogen peroxide, lipopolysaccharide, and epidermal growth factor. When examined for the mechanism of action, we found that picroliv inhibited activation of IkappaBalpha kinase, leading to inhibition of phosphorylation and degradation of IkappaBalpha. It also inhibited phosphorylation and nuclear translocation of p65. Further studies revealed that picroliv directly inhibits the binding of p65 to DNA, which was reversed by the treatment with reducing agents, suggesting a role for a cysteine residue in interaction with picroliv. Mutation of Cys(38) in p65 to serine abolished this effect of picroliv. NF-kappaB inhibition by picroliv leads to suppression of NF-kappaB-regulated proteins, including those linked with cell survival (inhibitor of apoptosis protein 1, Bcl-2, Bcl-xL, survivin, and TNF receptor-associated factor 2), proliferation (cyclin D1 and cyclooxygenase-2), angiogenesis (vascular endothelial growth factor), and invasion (intercellular adhesion molecule-1 and matrix metalloproteinase-9). Suppression of these proteins enhanced apoptosis induced by TNF. Overall, our results show that picroliv inhibits the NF-kappaB activation pathway, which may explain its anti-inflammatory and anticarcinogenic effects.
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PMID:Modification of cysteine residue in p65 subunit of nuclear factor-kappaB (NF-kappaB) by picroliv suppresses NF-kappaB-regulated gene products and potentiates apoptosis. 3018 11

The function of Ca(2+) and the calcium sensing receptor (CaSR) in breast epithelium and its relationship to mammary carcinogenesis is poorly understood. In this study, we determined the function of this ligand receptor system in regulating the biologic properties of the estrogen receptor-positive MCF-7 and the estrogen receptor-negative MDA-MB-435 human breast cancer cells. Physiologic concentration of extracellular Ca(2+) (by comparison to cells cultured in control low Ca(2+) medium) down-modulated cellular proliferation, cellular invasion and growth in soft agarose in both of these cell lines. Physiologic concentration of extracellular Ca(2+) also down-modulated the expression of the anti-apoptotic protein survivin, survivin gene transcriptional activity, survivin mRNA expression and promoted a cytotoxic response to paclitaxel. These responses to extracellular Ca(2+) were found to require CaSR expression because knocking down CaSR expression in these cells abrogated the cellular responses to extracellular Ca(2+). Each cell line was found to contain small subpopulations that did not express CaSR but expressed a higher level of survivin. These subpopulations were relatively resistant to paclitaxel by comparison to cells that expressed CaSR with a lower level of survivin expression. It is concluded that extracellular Ca(2+) and CaSR may constitute a robust ligand-receptor system in regulating the biologic phenotype of breast epithelial cells and loss of CaSR expression may promote malignancy and resistance to cytotoxic drugs.
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PMID:Calcium sensing receptor down-regulates malignant cell behavior and promotes chemosensitivity in human breast cancer cells. 1903 44

Ochratoxin A (OTA) is a potent renal carcinogen, but little is known regarding the mechanism of OTA carcinogenicity. Early histopathological alterations induced by OTA in rat kidney include single cell death, stimulation of cell proliferation and prominent karyomegaly indicative of blocked nuclear division during mitosis. Based on these observations, it has been suggested that disruption of mitosis by OTA may be the principal cause of cell death and subsequent trigger for cell proliferation to compensate for cell loss. To gain further insight into the molecular mechanism of OTA toxicity, we used targeted quantitative real-time polymerase chain reaction arrays to investigate the expression of genes involved in cell cycle control and mitosis in kidneys of male F344 rats treated with 0, 21, 70 and 210 microg/kg body wt OTA for up to 90 days. Treatment with OTA resulted in overexpression of key regulators of mitosis, including the mitotic protein kinases Polo-like kinase 1, Aurora B and cyclin-dependent kinase 1 (Cdk1Cdc2), several cyclins and cyclin-dependent kinase inhibitors, topoisomerase II and survivin. Immunohistochemical analysis confirmed upregulation of Cdk1, p21(WAF1/CIP1), topoisomerase II and survivin in S3 proximal tubule cells, from which OTA-induced tumors in rats arise, and demonstrated increased phosphorylation of histone H3, a target of Aurora B. Importantly, many of the genes found to be deregulated in response to OTA have been linked to chromosomal instability and malignant transformation, supporting the hypothesis that aberrant mitosis, resulting in blocked or asymmetric cell division, accompanied by an increased risk of aneuploidy acquisition, may play a critical role in OTA carcinogenicity.
Carcinogenesis 2009 Apr
PMID:Modulation of key regulators of mitosis linked to chromosomal instability is an early event in ochratoxin A carcinogenicity. 1923 4

Bcl-x(L) is one of several antiapoptotic proteins regulated by signal transducer and activator of transcription 3 (Stat3). We have recently shown that Stat3 is required for chemically induced and ultraviolet B (UVB)-induced skin carcinogenesis. In this study, the functional role of Bcl-x(L) in skin carcinogenesis was investigated using skin-specific Bcl-x(L)-deficient mice. In this model, Bcl-x(L) expression is disrupted in the basal compartment of mouse epidermis using the bovine keratin 5 (K5) promoter to drive expression of Cre recombinase (K5.Cre x Bcl-x(L) (fl/fl) mice). A significant increase in apoptosis induced by either UVB irradiation or 7,12-dimethylbenz[a]anthracene (DMBA) treatment was observed in the epidermis of Bcl-x(L)-deficient mice. Furthermore, an increase in apoptotic cells was noted in hair follicle keratinocytes, including those located in the bulge region. Cell proliferation was not affected by Bcl-x(L) deficiency following exposure to either UVB or 12-O-tetradecanoylphorbol-13-acetate (TPA). Bcl-x(L)-deficient mice were more resistant than wild-type controls to skin tumor development with delayed onset and reduced number of tumors using either UVB or the DMBA/TPA two-stage regimen. Moreover, Bcl-2, Mcl-1, and survivin protein levels were increased in the epidermis of Bcl-x(L)-deficient mice in the absence of stimuli. Furthermore, levels of these antiapoptotic proteins were also high in skin tumors from Bcl-x(L)-deficient mice that developed in response to either UVB or two-stage carcinogenesis protocols. Collectively, these studies demonstrate that Bcl-x(L) plays a role early in skin carcinogenesis through its anti-apoptotic functions to enhance survival of keratinocytes, including bulge region keratinocyte stem cells, following DNA damage.
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PMID:Targeted disruption of Bcl-xL in mouse keratinocytes inhibits both UVB- and chemically induced skin carcinogenesis. 1930

Survivin is a bi-functional member of inhibitor of apoptosis protein family, as it is able to both inhibit apoptosis and to regulate cell cycle. We investigated the role of survivin in human keratinocytes under normal conditions and during UVB irradiation. Survivin siRNA decreases proliferation and induces apoptosis in human keratinocytes, in a mode consistent with the mitotic catastrophe. Low doses UVB increase survivin expression at earlier times, while high doses down-regulate survivin level. Low doses UVB induce cell cycle arrest in G2/M, while high doses UVB cause apoptosis. Moreover, overexpression of survivin protects keratinocytes from UVB-induced apoptosis, and silencing of survivin renders keratinocytes more susceptible to UVB-induced cell death. Finally, survivin siRNA increases UVB-induced reduction of cell proliferation. Taken together, these results indicate that survivin plays a critical role in epidermal homeostasis in normal conditions and during UVB exposure, with possible implication in skin carcinogenesis.
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PMID:Endogenous survivin modulates survival and proliferation in UVB-treated human keratinocytes. 1932 Jul 41

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