Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Androgen antagonists or androgen deprivation are the primary therapeutic modalities for the treatment of prostate cancer. Invariably, however, the disease becomes progressive and unresponsive to androgen ablation therapy (hormone refractory). The molecular mechanisms by which androgen antagonists inhibit prostate cancer proliferation are not fully defined. In this study, we identify two molecules which are required for effective prostate cancer cell responsiveness to androgen antagonists. We establish that androgen receptor (AR)-dependent transcriptional suppression by androgen antagonists requires the tumor suppressor prohibitin. This requirement for prohibitin was demonstrated using structurally-distinct androgen antagonists, stable and transient knockdown of prohibitin and transfected and endogenous AR-responsive genes. The SWI-SNF complex core ATPase BRG1, but not its closely-related counterpart ATPase BRM, is required for this repressive action of prohibitin on AR-responsive promoters. Androgen antagonists induce recruitment of prohibitin and BRG1 to endogenous AR-responsive promoters and induce a physical association between AR and prohibitin and BRG1. The recruitment of prohibitin to endogenous AR-responsive promoters is dependent upon antagonist-bound AR. Prohibitin binding in the prostate-specific antigen (PSA) promoter results in the recruitment of BRG1 and the dissociation of p300 from the PSA promoter. These findings suggest that prohibitin may function through BRG1-mediated local chromatin remodeling activity and the removal of p300-mediated acetylation to produce androgen antagonist-mediated transcriptional repression. Furthermore, in addition to its necessary role in AR-mediated transcriptional repression, we demonstrate that prohibitin is required for full and efficient androgen antagonist-mediated growth suppression of prostate cancer cells.
Carcinogenesis 2008 Sep
PMID:Prohibitin and the SWI/SNF ATPase subunit BRG1 are required for effective androgen antagonist-mediated transcriptional repression of androgen receptor-regulated genes. 1848 22

Topoisomerases are targets of several anticancer agents because their inhibition impedes the processes of cell proliferation and differentiation in carcinogenesis. With very limited information available on the inhibitory activities of peptides derived from dietary proteins, the objectives of this study were to employ co-immunoprecipitation to identify inhibitory peptides in soy protein hydrolysates in a single step and to investigate their molecular interactions with topoisomerase II. For this, soy protein isolates were subjected to simulated gastrointestinal digestion with pepsin and pancreatin, and the human topoisomerase II inhibitory peptides were co-immunoprecipitated and identified on a CapLC- Micromass Q-TOF Ultima API system. The inhibitory activity of these peptides from soy isolates toward topoisomerase II was confirmed using three synthetic peptides, FEITPEKNPQ, IETWNPNNKP,and VFDGEL, which have IC 50 values of 2.4, 4.0, and 7.9 mM, respectively. The molecular interactions of these peptides evaluated by molecular docking revealed interaction energies with the topoisomerase II C-terminal domain (CTD) (-186 to -398 kcal/mol) that were smaller than for the ATPase domain (-169 to -357 kcal/mol) and that correlated well with our experimental IC 50 values ( R (2) = 0.99). In conclusion, three peptides released from in vitro gastrointestinal enzyme digestion of soy proteins inhibited human topoisomerase II activity through binding to the active site of the CTD domain.
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PMID:Identification and characterization of topoisomerase II inhibitory peptides from soy protein hydrolysates. 1859 77

SWI/SNF is a chromatin-remodelling complex that makes DNA that has been compacted into nucleosomes accessible to transcription factors and repair enzymes. It does this by displacing DNA from the core histone surface. SWI/SNF consists of at least nine subunits, including one of two alternative ATPase subunits, BRM or BRG-1, that provide the energy for remodelling. As it regulates access to DNA it controls many aspects of normal cellular function. Limited studies have recently linked loss of function of SWI/SNF subunits to cancer development, suggesting that it may be a tumor suppressor complex. As epigenetic repression regulates SWI/SNF component expression at least in some cases, restoration of function is therapeutically promising for cancer treatment. Considerably more research is required into deregulation of SWI/SNF in cancer and determination of how this affects tumor development. This is an exciting but poorly understood molecule that may have a role in carcinogenesis.
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PMID:SWI/SNF: a chromatin-remodelling complex with a role in carcinogenesis. 1872 14

Palytoxin is classified as a non-12-O-tetradecanoylphorbol-13-acetate (TPA)-type skin tumor because it does not bind to or activate protein kinase C. Palytoxin is thus a novel tool for investigating alternative signaling pathways that may affect carcinogenesis. We previously showed that palytoxin activates three major members of the mitogen activated protein kinase (MAPK) family, extracellular signal regulated kinase 1 and 2 (ERK1/2), c-Jun N-terminal kinase (JNK), and p38. Here we report that palytoxin also activates another MAPK family member, called ERK5, in HeLa cells and in keratinocytes derived from initiated mouse skin (308 cells). By contrast, TPA does not activate ERK5 in these cell lines. The major cell surface receptor for palytoxin is the Na+,K+-ATPase. Accordingly, ouabain blocked the ability of palytoxin to activate ERK5. Ouabain alone did not activate ERK5. ERK5 thus represents a divergence in the signaling pathways activated by these two agents that bind to the Na+,K+-ATPase. Cycloheximide, okadaic acid, and sodium orthovanadate did not mimic the effect of palytoxin on ERK5. These results indicate that the stimulation of ERK5 by palytoxin is not simply due to inhibition of protein synthesis or inhibition of serine/threonine or tyrosine phosphatases. Therefore, the mechanism by which palytoxin activates ERK5 differs from that by which it activates ERK1/2, JNK, and p38. Finally, studies that used pharmacological inhibitors and shRNA to block ERK5 action indicate that ERK5 contributes to palytoxin-stimulated c-Fos gene expression. These results suggest that ERK5 can act as an alternative mediator for transmitting diverse tumor promoter-stimulated signals.
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PMID:Extracellular signal regulated kinase 5 mediates signals triggered by the novel tumor promoter palytoxin. 1971 39

FXYD3 is a FXYD-containing Na,K-ATPase ion channel regulator first identified as a protein overexpressed in murine breast tumors initiated by oncogenic ras or neu. However, our preliminary study revealed that FXYD3 expression was down-regulated in oncogenic KRAS-transduced airway epithelial cells. This contradiction led us to investigate the role of FXYD3 in carcinogenesis of the lung. FXYD3 mRNA and protein levels were lower in most of the lung cancer cell lines than in either the noncancerous lung tissue or airway epithelial cells. Protein levels were also lower in a considerable proportion of primary lung cancers than in nontumoral airway epithelia; FXYD3 expression levels decreased in parallel with the dedifferentiation process. Also, a somatic point mutation, g55c (D19H), was found in one cell line. Forced expression of the wild-type FXYD3, but not the mutant, restored the well-demarcated distribution of cortical actin in cancer cells that had lost FXYD3 expression, suggesting FXYD3 plays a role in the maintenance of cytoskeletal integrity. However, no association between FXYD3 expression and its promoter's methylation status was observed. Therefore, inactivation of FXYD3 through a gene mutation or unknown mechanism could be one cause of the atypical shapes of cancer cells and play a potential role in the progression of lung cancer.
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PMID:Down-regulation of FXYD3 expression in human lung cancers: its mechanism and potential role in carcinogenesis. 1989 46

Aim of the present study was to investigate the protective effect of Clerodendron inerme on cellular integrity by measuring the status of glycoconjugates, lipids, osmotic fragility, and membrane bound enzyme activity in 7,12-dimethylbenz (a) anthracene (DMBA)-induced oral carcinogenesis. Oral squamous cell carcinoma was induced in the buccal pouch of Syrian golden hamsters by painting with 0.5% DMBA in liquid paraffin thrice a week for 14 weeks. The levels of glycoconjugates, lipids, osmotic fragility and membrane bound enzyme activity were analyzed by using specific colorimetric methods. We observed 100% tumor formation in DMBA painted hamsters. Altered glycoconjugates and lipid pattern were observed in DMBA painted hamsters as compared to control hamsters. Erythrocytes from DMBA painted hamsters were more fragile than those from control hamsters. The activity of membrane bound enzyme (Na(+) K(+) ATPase) decreased in DMBA painted hamsters as compared to control hamsters. Oral administration of aqueous leaf extract of Clerodendron inerme (CiALet) at a dose of 500 mg/kg body weight significantly prevented the tumor formation and histopathological abnormalities as well as normalized the above said biochemical variables in DMBA painted hamsters. Our results thus demonstrate the protective effect of Clerodendron inerme on cellular integrity during DMBA induced oral carcinogenesis.
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PMID:Clerodendron inerme protects cellular integrity during 7,12-dimethylbenz[A]-anthracene induced hamster buccal pouch carcinogenesis. 2016 40

The aim of the present study was to investigate the protective effect of Withaferin-A on red blood cell integrity during 7,12-dimethylbenz[a]anthracene (DMBA) induced oral carcinogenesis. The protective effect of Withaferin-A was assessed by measuring the status of glycoconjugates, membrane bound enzyme activity and red blood cell osmotic fragility. Oral squamous cell carcinoma was induced in the buccal pouch of Syrian golden hamsters by painting with 0.5% DMBA in liquid paraffin thrice a week for 14 weeks. The levels of glycoconjugates, membrane bound enzyme activity, osmotic fragility and thiobarbituric acid reactive substances (TBARS) were analyzed by using specific colorimetric methods. We observed 100% tumor formation in DMBA painted hamsters. Increase in plasma glycoconjugates at the expense of red blood cell membrane glycoconjugates levels were observed in DMBA painted hamsters as compared to control hamsters. Erythrocytes from DMBA painted hamsters were more fragile than those from control hamsters. The activity of membrane bound enzyme (Na(+) K(+) ATPase) decreased whereas TBARS level was increased in DMBA painted hamsters as compared to control hamsters. Oral administration of Withaferin-A at a dose of 20 mg kg(-1) bw significantly prevented the tumor formation as well as normalized the biochemical variables in DMBA painted hamsters. Our results thus demonstrate the protective effect of Withaferin-A on red blood cell integrity during DMBA induced oral carcinogenesis.
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PMID:Protective role of Withaferin-A on red blood cell integrity during 7,12-dimethylbenz[a]anthracene induced oral carcinogenesis. 2016 47

Evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cycloxygenase (COX) and production of the proinflammatory prostaglandin, PGE2, and thus prevent carcinogenesis in the colon. Indeed, one of the specific COX-2 inhibitors, celecoxib, had been accepted by the US FDA for the treatment of familial adenomatous polyposis. However, the molecular mechanism of such inhibition is not clear, although apoptosis appears to be the dominant antiproliferative end effect. The present study delineates the intracellular ionic milieu in the colonocytes that could generate strong apoptotic signals where DMH-induced carcinogenesis was studied in the initiation stage in rats and its regression with the COX inhibitors. While DMH treatment produced a significant elevation in the Na+/H+ exchanger activity and resultant proton efflux, this was reversed by the NSAIDs, particularly so with celecoxib and etoricoxib compared to aspirin. Similarly, the intracellular pH was changed, with more alkalosis noted in DMH, which was reversed by NSAIDs. Also, an intracellular Ca2+ build up was noted by Fura 2 AM, which was also supported by a reduced Ca2+ ATPase and an enhanced inward movement of Ca2+. Further, mitochondrial dysfunction-related cyt C release, increased DNA ladder formation, activation of caspase-3, and cleavage product of poly (ADP-ribose) polymerase (PARP) were not seen in DMH but well noted in NSAIDs. Our results indicate that NSAIDs can induce apoptosis through a change in the colonic Na+/H+ exchange, intracellular pH, and an unfavorable Ca2+ homeostasis.
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PMID:Na(+)-stimulated Na+/H+ exchange and an unfavorable Ca2+ homeostasis initiate the cycloxygenase-2 inhibitors-induced apoptotic signals in colonic epithelial cells during the early stage of colon carcinogenesis. 2022 62

In addition to hormonal activity, genetic damage has been proposed as an important factor in oestrogen-mediated carcinogenesis. However, as short-term tests for oestrogens usually fail to show DNA mutations, lesions other than classic nuclear DNA mutation have to be considered. Oestrogen-induced mitochondrial damage was studied in the yeast Saccharomyces cerevisiae. Stilbene-type, but not steroidal, oestrogens were found to induce respiration-deficient petite mutation. The effect was inversely correlated with cytotoxicity and required aromatic hydroxyl groups at the stilbene molecule. It only occurred under growth conditions and apparently was not due to the ATPase inhibitory qualities of stilbene oestrogens. Other studies have shown that petite mutation clones, which can be induced by a variety of substances, contain altered mitochondrial DNA. The mechanism of petite mutation induction might be important in tumorigenesis by also acting on nuclear DNA or facilitating carcinogenesis by disturbance of mitochondrial function.
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PMID:Carcinogenic oestrogens induce respiration deficiency mutation in yeast. 2073 62

Adenine nucleotide translocase (ANT), a mitochondrial protein that facilitates the exchange of ADP and ATP across the mitochondrial inner membrane, plays an essential role in cellular energy metabolism. Human ANT presents four isoforms (ANT1-4), each with a specific expression depending on the nature of the tissue, cell type, developmental stage and status of cell proliferation. Thus, ANT1 is specific to muscle and brain tissues; ANT2 occurs mainly in proliferative, undifferentiated cells; ANT3 is ubiquitous; and ANT4 is found in germ cells. ANT1 and ANT3 export the ATP produced by oxidative phosphorylation (OxPhos) from the mitochondria into the cytosol while importing ADP. In contrast, the expression of ANT2, which is linked to the rate of glycolytic metabolism, is an important indicator of carcinogenesis. In fact, cancers are characterized by major metabolic changes that switch cells from the normally dual oxidative and glycolytic metabolisms to an almost exclusively glycolytic metabolism. When OxPhos activity is impaired, ANT2 imports glycolytically produced ATP into the mitochondria. In the mitochondrial matrix, the F1F0-ATPase complex hydrolyzes the ATP, pumping out a proton into the intermembrane space. The reverse operations of ANT2 and F1F0-ATPase under glycolytic conditions contribute to maintaining the mitochondrial membrane potential, ensuring cell survival and proliferation. Unlike the ANT1 and ANT3 isoforms, ANT2 is not pro-apoptotic and may therefore contribute to carcinogenesis. Since the expression of ANT2 is closely linked to the mitochondrial bioenergetics of tumors, it should be taken into account for individualizing cancer treatments and for the development of anticancer strategies.
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PMID:Adenine nucleotide translocase 2 is a key mitochondrial protein in cancer metabolism. 2095 May 84


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