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)

BTG2/TIS21/PC3 (B cell translocation gene 2) has been known as a p53 target gene and functions as a tumor suppressor in carcinogenesis of thymus, prostate, kidney, and liver. Although it has been known that the expression of BTG2/TIS21/PC3 is induced during chemotherapy-mediated apoptosis in cancer cells, a role of BTG2/TIS21/PC3 in cell death remains to be elucidated. In this study, the mechanism and role of BTG2 involved in the enhancement of doxorubicin (DOXO)-induced cell death were examined. Treatment of HeLa cells with DOXO revealed apoptotic phenomena, such as chromatin condensation and cleavage of poly(ADP-ribose) polymerase and lamin A/C with concomitant increase of BTG2/TIS21/PC3 expression. Employing infections of Ad-TIS21 virus and lentivirus with short hairpin RNA to BTG2, the effect of BTG2/TIS21/PC3 on the DOXO-induced apoptosis of HeLa cells and liver cancer cells was evaluated. Not only short hairpin RNA-BTG2 but also N-acetyl-L-cysteine significantly reduced the DOXO-induced HeLa cell death and generation of H2O2. Moreover, forced expression of BTG2/TIS21/PC3 using adenoviral vector augmented DOXO-induced cancer cell death concomitantly with increase of manganese-superoxide dismutase but not catalase, CuZnSOD, and glutathione peroxidase 1. The increased apoptosis by forced expression of BTG2/TIS21/PC3 could be inhibited by N-acetyl-L-cysteine and polyethylene glycol-catalase. These results therefore suggest that BTG2/TIS21/PC3 works as an enhancer of DOXO-induced cell death via accumulation of H2O2 by up-regulating manganese-superoxide dismutase without any other antioxidant enzymes. In summary, BTG2/TIS21/PC3 enhances cancer cell death by accumulating H2O2 via imbalance of the antioxidant enzymes in response to chemotherapy.
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PMID:B cell translocation gene 2 enhances susceptibility of HeLa cells to doxorubicin-induced oxidative damage. 1884 Jun 9

Subtypes of breast cancer that represent the two major types of epithelial cells in the breast (luminal and basal) carry distinct histopathologic profiles. Breast cancers of the basal-like subtype, which include the majority of hereditary breast cancers due to mutations in the breast cancer susceptibility gene 1 (BRCA1), frequently assume triple-negative status, i.e., they lack expression of estrogen receptor-alpha and progesterone receptor, and lack overexpression or amplification of the HER2/NEU oncogene. Defects in DNA damage response pathways result in genome instability and lead to carcinogenesis, but may also be exploited for therapeutic purposes. We analyzed repair of oxidative DNA damage by the base-excision repair (BER) pathway, which when aberrant leads to genomic instability and breast carcinogenesis, in cell lines that represent the different subtypes of breast cancer and in the presence of BRCA1 deficiency. We found that basal-like and BRCA1-mutated breast cancer cells were defective in BER of oxidative DNA damage, and that this defect conferred sensitivity to inhibition of poly(ADP-ribose) polymerase, a DNA repair enzyme. The defect may be attributed, at least in part, to a novel role for BRCA1 in the BER pathway. Overall, these data offer preventive, prognostic, and therapeutic usefulness.
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PMID:Defective repair of oxidative dna damage in triple-negative breast cancer confers sensitivity to inhibition of poly(ADP-ribose) polymerase. 1935 35

Limonoids from the neem tree (Azadirachta indica) have attracted considerable research attention for their cytotoxicity against human cancer cell lines. However, the antiproliferative and apoptosis inducing effects of neem limonoids have not been tested in animal tumour models. The present study was therefore designed to evaluate the relative chemopreventive potential of the neem limonoids azadirachtin and nimbolide in the hamster buccal pouch (HBP) carcinogenesis model by analyzing the expression of proliferating cell nuclear antigen (PCNA), p21(waf1), cyclin D1, glutathione S-transferase pi (GST-P), NF-kappaB, inhibitor of kappaB (IkappaB), p53, Fas, Bcl-2, Bax, Bid, Apaf-1, cytochrome C, survivin, caspases-3, -6, -8 and -9, and poly(ADP-ribose) polymerase (PARP) by RT-PCR, immunohistochemical, and Western blot analyses. The results provide compelling evidence that azadirachtin and nimbolide mediate their antiproliferative effects by downregulating proteins involved in cell cycle progression and transduce apoptosis by both the intrinsic and extrinsic pathways. On a comparative basis, nimbolide was found to be a more potent antiproliferative and apoptosis inducing agent and offers promise as a candidate agent in multitargeted prevention and treatment of cancer.
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PMID:The neem limonoids azadirachtin and nimbolide inhibit cell proliferation and induce apoptosis in an animal model of oral oncogenesis. 1945 12

XAF1 (X chromosome-linked inhibitor of apoptosis [XIAP]-associated factor 1) is a novel XIAP modulator that negatively regulates the anti-apoptotic effects of XIAP and sensitizes cells to other cell death triggers. It has been reported to be downregulated in a variety of human cancer cell lines. However, the role of XAF1 in pancreatic carcinogenesis remains unclear. In the present study, we investigated the prognostic values of XAF1 expression and its regulation in cancer cell growth and apoptosis both in vitro and in vivo. From the immunohistochemistry staining of tissue microarray, 40 of 89 (44.9%) pancreatic specimens showed low levels of XAF1 expression. Statistical analysis suggested the downregulation of XAF1 was significantly correlated with tumor staging (P = 0.047) and those patients with low XAF1 levels had shorter survival times (P = 0.0162). Multivariate analysis indicated that XAF1 expression was an independent prognostic indicator of the survival of patients with pancreatic cancer (P = 0.007). Furthermore, we found that restoration of XAF1 expression mediated by Ad5/F35 virus suppressed cell proliferation and induced cell cycle arrest and apoptosis, accompanied by the activation of caspases 3, 8, and 9 and poly(ADP-ribose) polymerase as well as increased level of cytochrome c and Bid cleavage. Notably, XAF1 restoration robustly decreased survivin expression rather than XIAP. In addition, in vivo s.c. xenografts from Ad5/F35-XAF1 treatment, which showed less cellular proliferation and enhanced apoptosis, were significantly smaller than those from control groups. Our findings document that XAF1 is a valuable prognostic marker in pancreatic cancer and could be a potential candidate for cancer gene therapy.
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PMID:XAF1 as a prognostic biomarker and therapeutic target in pancreatic cancer. 1992 3

The class III histone deacetylase (HDAC) SIRT1 plays a role in the metabolism, aging, and carcinogenesis of organisms and regulates senescence and apoptosis in cells. Recent reports revealed that SIRT1 also deacetylates several DNA double-strand break (DSB) repair proteins. However, its exact functions in DNA repair remained elusive. Using nuclear foci analysis and fluorescence-based, chromosomal DSB repair reporter, we find that SIRT1 activity promotes homologous recombination (HR) in human cells. Importantly, this effect is unrelated to functions of poly(ADP-ribose) polymerase 1 (PARP1), another NAD(+)-catabolic protein, and does not correlate with cell cycle changes or apoptosis. Interestingly, we demonstrate that inactivation of Rad51 does not eliminate the effect of SIRT1 on HR. By epistasis-like analysis through knockdown and use of mutant cells of distinct SIRT1 target proteins, we show that the non-homologous end joining (NHEJ) factor Ku70 as well as the Nijmegen Breakage Syndrome protein (nibrin) are not needed for this SIRT1-mediated effect, even though a partial contribution of nibrin cannot be excluded. Strikingly however, the Werner helicase (WRN), which in its mutated form causes premature aging and cancer and which was linked to the Rad51-independent single-strand annealing (SSA) DSB repair pathway, is required for SIRT1-mediated HR. These results provide first evidence that links SIRT1's functions to HR with possible implications for genomic stability during aging and tumorigenesis.
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PMID:Role of SIRT1 in homologous recombination. 2009 25

Cancer chemoprevention is thought to occur either by blocking the initiation of or suppressing the promotion of carcinogenesis. Phase II detoxification enzymes are known to play important roles in cancer chemoprevention because they enhance cytoprotection through detoxification and elimination of activated carcinogens at tumor initiation. Apoptosis is one of the most important inhibitory targets for tumor promotion. In this study, we have investigated the cancer chemopreventive activity of the ethanolic extract of Carpesium abrotanoides (CAE). We found that CAE induced quinone reductase [also known as NAD(P)H:quinone oxidoreductase (NQO1)] activity, increased NQO1 mRNA and protein expression, and had a relatively high chemoprevention index (12.04). CAE also significantly activated the antioxidant response element through the nuclear accumulation of NF-E2-related factor 2 in HCT116. Interestingly, we also found that CAE induced apoptosis, as evidenced by the externalization of phosphatidylserine, increased sub-G(0)/G(1) content, chromatin condensation, poly(ADP-ribose) polymerase cleavage, and p53. These data suggest that the chemopreventive effects of C. abrotanoides can result from both the induction of phase II detoxification enzymes and from apoptosis. Thus, CAE could potentially be developed as a cancer chemopreventive agent for prevention or treatment of human cancers.
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PMID:The chemopreventive effects of Carpesium abrotanoides are mediated by induction of phase II detoxification enzymes and apoptosis in human colorectal cancer cells. 2013 34

Asbestos carcinogenesis has been linked to the release of cytokines and mutagenic reactive oxygen species (ROS) from inflammatory cells. Asbestos is cytotoxic to human mesothelial cells (HM), which appears counterintuitive for a carcinogen. We show that asbestos-induced HM cell death is a regulated form of necrosis that links to carcinogenesis. Asbestos-exposed HM activate poly(ADP-ribose) polymerase, secrete H(2)O(2), deplete ATP, and translocate high-mobility group box 1 protein (HMGB1) from the nucleus to the cytoplasm, and into the extracellular space. The release of HMGB1 induces macrophages to secrete TNF-alpha, which protects HM from asbestos-induced cell death and triggers a chronic inflammatory response; both favor HM transformation. In both mice and hamsters injected with asbestos, HMGB1 was specifically detected in the nuclei, cytoplasm, and extracellular space of mesothelial and inflammatory cells around asbestos deposits. TNF-alpha was coexpressed in the same areas. HMGB1 levels in asbestos-exposed individuals were significantly higher than in nonexposed controls (P < 0.0001). Our findings identify the release of HMGB1 as a critical initial step in the pathogenesis of asbestos-related disease, and provide mechanistic links between asbestos-induced cell death, chronic inflammation, and carcinogenesis. Chemopreventive approaches aimed at inhibiting the chronic inflammatory response, and especially blocking HMGB1, may decrease the risk of malignant mesothelioma among asbestos-exposed cohorts.
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PMID:Programmed necrosis induced by asbestos in human mesothelial cells causes high-mobility group box 1 protein release and resultant inflammation. 2061 36

Poly(ADP-ribose) metabolism, mediated mainly by poly(ADP-ribose) polymerase (PARP) 1 and poly(ADP-ribose) glycohydrolase (PARG), regulates various cellular processes in response to genotoxic stress. PARP1 has been shown to be important in multiple cellular processes, including DNA repair, chromosomal stability, chromatin function, apoptosis and transcriptional regulation. However, whether PARP1's polymer synthesizing activity or polymer homeostasis is responsible for these functions remains largely unknown. Given a concerted action of multiple PARPs and unique PARG in the homeostasis of poly(ADP-ribosyl)ation, PARG is hypothesized to function in these processes. The lethal phenotype of the PARG null mutation in mouse embryos, however, hampers further investigation on biological function of PARG. Here, we show that mouse embryonic fibroblasts carrying a hypomorphic mutation of PARG, i.e. lacking the nuclear 110 kD isoform (PARG(110)(-/-)), have defects in the repair of DNA damage caused by various genotoxic agents. PARG(110)(-/-) cells exhibit genomic instability, characterized by a high frequency of sister chromatid exchange, micronuclei formation and chromosomal aberrations. Moreover, mutant cells contain supernumerary centrosomes, another hallmark of genomic instability, which correlates with an accumulation of S-phase cells after replication poison. Intriguingly, PARG(110)(-/-) cells accumulate more Rad51 foci in response to hydroxyurea, indicative of a defective repair of replication fork damage. Finally, PARG(110)(-/-) mice are susceptible to diethylnitrosamine-induced hepatocellular carcinoma. These data demonstrate that the homeostasis of poly(ADP-ribosyl)ation is important for an efficient DNA repair of damaged replication forks and for stabilizing the genome, thereby preventing carcinogenesis.
Carcinogenesis 2010 Dec
PMID:Deletion of the nuclear isoform of poly(ADP-ribose) glycohydrolase (PARG) reveals its function in DNA repair, genomic stability and tumorigenesis. 2092 29

Prostate cancer is the second leading cause of cancer-associated deaths among men in the western countries. Here, we report that human RecQL4 helicase, which is implicated in the pathogenesis of a subset of cancer-prone Rothmund-Thomson syndrome, is highly elevated in metastatic prostate cancer cell lines. Increased RecQL4 expression was also detected in human prostate tumor tissues as a function of tumor grade with the highest expression level in metastatic tumor samples, suggesting that RecQL4 may be a potential prognostic factor for advanced stage of prostate cancer. Transient and stable suppression of RecQL4 by small interfering RNA and short hairpin RNA vectors drastically reduced the growth and survival of metastatic prostate cancer cells, indicating that RecQL4 is a prosurvival factor for prostate cancer cells. RecQL4 suppression led to increased poly(ADP-ribose) polymerase (PARP) synthesis and RecQL4-suppressed prostate cancer cells underwent an extensive apoptotic death in a PARP-1-dependent manner. Most notably, RecQL4 knockdown in metastatic prostate cancer cells drastically reduced their cell invasiveness in vitro and tumorigenicity in vivo, showing that RecQL4 is essential for prostate cancer promotion. Observation of a direct interaction of retinoblastoma (Rb) and E2F1 proteins with RecQL4 promoter suggests that Rb-E2F1 pathway may regulate RecQL4 expression. Collectively, our study shows that RecQL4 is an essential factor for prostate carcinogenesis.
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PMID:Human RecQL4 helicase plays critical roles in prostate carcinogenesis. 2104 46

The nuclear matrix displays the most dramatic changes among all cellular structures during carcinogenesis. Matrix attachment regions (MARs) organize chromatin into domains, harbor origins of replication and display a notable transcriptional enhancer activity. To understand the nature of MARs and their involvement in gene expression, replication, and carcinogenesis, we have cloned the MAR DNA fragments, of a size of 0.1-5.0 kb, isolated from human cells in culture. Over 150 clones have been sequenced. One MAR clone was identified as a stretch of 393 bp from the 3' untranslated region (3' UTR) of the human poly(ADP-ribose) polymerase (PARR) gene (100% homology). The 393 bp MAR fragment contains several repeats of TTGTTTTGT and related sequences (the TG boxes) and motifs with similarity to the binding site of the general yeast transcription factor GFI and to the ARS origins of replication in yeast. In addition, the 3' UTR of the PARP gene harbors MAR-type sequences found in other genes, kinked and curved DNA, two imperfect inverted repeats, and short alternating GA- and CT-rich motifs. The presence of TG-, GA-, and CT-rich motifs and of potential cruciforms is proposed to identify a novel type of MAR sequence. This report suggests that MAR sequences may reside in the 3' untranslated region of other genes and has important implications for a potential role of the nuclear matrix in transcription termination.
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PMID:The 3' untranslated region of the human poly(ADP-ribose) polymerase gene is a nuclear matrix anchoring site. 2154 39


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