Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A growing number of reports indicate the frequent presence of DNA sequences and gene products of human cytomegalovirus in various tumors as compared to adjacent normal tissues, the brain tumors being studied most intensely. The mechanisms underlying the tropism of human cytomegalovirus to the tumor cells or to the cells of tumor origin, as well as the role of the host's genetic background in virus-associated oncogenesis are not well understood. It is also not clear why cytomegalovirus can be detected in many but not in all tumor specimens. Our in silico prediction results indicate that microRNA-34a may be involved in replication of some human DNA viruses by targeting and downregulating the genes encoding a diverse group of proteins, such as platelet-derived growth factor receptor-alpha, complement component receptor 2, herpes simplex virus entry mediators A, B, and C, and CD46. Notably, while their functions vary, these surface molecules have one feature in common: they serve as cellular entry receptors for human DNA viruses (cytomegalovirus, Epstein-Barr virus, human herpes virus 6, herpes simplex viruses 1 and 2, and adenoviruses) that are either proven or suspected to be linked with malignancies. MicroRNA-34a is strictly dependent on its transcriptional activator tumor suppressor protein p53, and both p53 and microRNA-34a are frequently mutated or downregulated in various cancers. We hypothesize that p53-microRNA-34a axis may alter susceptibility of cells to infection with some viruses that are detected in tumors and either proven or suspected to be associated with tumor initiation and progression.
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PMID:The p53-microRNA-34a axis regulates cellular entry receptors for tumor-associated human herpes viruses. 2364 4

Nowadays cancer is still a major public health issue. Despite all the progresses made in cancer prevention, diagnosis and treatment, mortality by cancer is on the second place after the one caused by cardiovascular diseases. The high mortality and the increasing incidence of certain cancers (lung, prostate, colorectal) justify a growing interest for the identification of new pharmacological agents efficient in cancer prevention and treatment. In the last fifty years many plant-derived agents (vinblastine, vincristine, vindesine, paclitaxel, docetaxel, topotecan, irinotecan, elliptinium) played a major role in cancer treatment. Other very promising plant-derived anticancer agents (combrestatins, betulinic acid, roscovitine, purvalanols, indirubins) are in clinical or preclinical trials. Curcumin, a liposoluble polyphenolic pigment isolated from the rhizomes of Curcuma longa L. (Zingiberaceae), is another potential candidate for new anticancer drug development. Curcumin has been reported to influence many cell-signaling pathways involved in tumor initiation and proliferation. Curcumin inhibits COX-2 activity, cyclin D1 and MMPs overexpresion, NF-kB, STAT and TNF-alpha signaling pathways and regulates the expression of p53 tumor suppressing gene. Curcumin is well-tolerated but has a reduced systemic bioavailability. Polycurcumins (PCurc 8) and curcumin encapsulated in biodegradable polymeric nanoparticles (NanoCurc) showed higher bioavailability than curcumin together with a significant tumor growth inhibition in both in vitro and in vivo studies. BILITY.
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PMID:Plant-derived anticancer agents - curcumin in cancer prevention and treatment. 2370 Sep 16

Aryl hydrocarbon receptor (AHR), a cytosolic ligand-activated transcription factor, belongs to the member of bHLH/PAS family of heterodimeric transcriptional regulators and is widely expressed in a variety of animal species and humans. Recent animal and human data suggested that AHR is involved in various signaling pathways critical to cell normal homeostasis, which covers multiple aspects of physiology, such as cell proliferation and differentiation, gene regulation, cell motility and migration, inflammation and others. Dysregulation of these physiological processes is known to contribute to events such as tumor initiation, promotion, and progression. Increasing epidemiological and experimental animal data provided substantial support for an association between abnormal AHR function and cancer, implicating AHR may be a novel drug-interfering target for cancers. The proposed underlying mechanisms of its actions in cancer involved multiple aspects, (a) inhibiting the functional expression of the key anti-oncogenes (such as p53 and BRCA1), (b) promoting stem cells transforming and angiogenesis, (c) altering cell survival, proliferation and differentiation by influencing the physiologic processes of cell-cycle, apoptosis, cell contact-inhibition, metabolism and remodel of extracellular matrix, and cell-matrix interaction, (d) cross-talking with the signaling pathways of estrogen receptor and inflammation. This review aims to provide a brief overview of recent investigations into the role of AHR and the underlying mechanisms of its actions in cancer, which were explored by the new technologies emerging in recent years.
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PMID:Role of aryl hydrocarbon receptor in cancer. 2371 59

Cancer stem cells (CSCs) are able to self-renew and are refractory to cancer treatment. To investigate the effects of resveratrol on CSCs of nasopharyngeal carcinoma (NPC), we employed a behavior selection strategy to isolate CSCs based on radioresistance, chemoresistance, and tumor sphere formation ability. These NPC CSCs displayed stem cell properties and underwent metabolic shift to predominately rely on glycolysis for energy supply. Intriguingly, we found that resveratrol turned off the metabolic switch, increased the reactive oxygen species (ROS) level, and depolarized mitochondrial membranes. These alterations in metabolism occurred concomitantly with the suppression of CSC properties including resistance to therapy, self-renewal capacity, tumor initiation capacity, and metastatic potential in NPC CSCs. We found that resveratrol impeded CSC properties through the activation of p53 and this effect could be reversed by knockdown of p53. Furthermore, resveratrol suppressed the stemness and EMT through reactivating p53 and inducing miR-145 and miR-200c, which were downregulated in NPC CSCs. In conclusion, we demonstrated that resveratrol employed the p53 pathway in regulating stemness, EMT, and metabolic reprogramming. Further investigation of the molecular mechanism of p53 activation by resveratrol may provide useful information for the development of novel therapies for cancer treatment through targeting to CSCs.
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PMID:Resveratrol Impedes the Stemness, Epithelial-Mesenchymal Transition, and Metabolic Reprogramming of Cancer Stem Cells in Nasopharyngeal Carcinoma through p53 Activation. 2373 38

We show that BRAF(V600E) initiates an alternative pathway to colorectal cancer (CRC), which progresses through a hyperplasia/adenoma/carcinoma sequence. This pathway underlies significant subsets of CRCs with distinctive pathomorphologic/genetic/epidemiologic/clinical characteristics. Genetic and functional analyses in mice revealed a series of stage-specific molecular alterations driving different phases of tumor evolution and uncovered mechanisms underlying this stage specificity. We further demonstrate dose-dependent effects of oncogenic signaling, with physiologic Braf(V600E) expression being sufficient for hyperplasia induction, but later stage intensified Mapk-signaling driving both tumor progression and activation of intrinsic tumor suppression. Such phenomena explain, for example, the inability of p53 to restrain tumor initiation as well as its importance in invasiveness control, and the late stage specificity of its somatic mutation. Finally, systematic drug screening revealed sensitivity of this CRC subtype to targeted therapeutics, including Mek or combinatorial PI3K/Braf inhibition.
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PMID:A genetic progression model of Braf(V600E)-induced intestinal tumorigenesis reveals targets for therapeutic intervention. 2384 41

Infiltrating macrophages are a key component of inflammation during tumorigenesis, but the direct evidence of such linkage remains unclear. We report here that persistent coculturing of immortalized prostate epithelial cells with macrophages, without adding any carcinogens, induces prostate tumorigenesis and that induction involves the alteration of signaling of macrophage androgen receptor (AR)-inflammatory chemokine CCL4-STAT3 activation as well as epithelial-to-mesenchymal transition and downregulation of p53/PTEN tumor suppressors. In vivo studies further showed that PTEN(+/-) mice lacking macrophage AR developed far fewer prostatic intraepithelial neoplasia (PIN) lesions, supporting an in vivo role for macrophage AR during prostate tumorigenesis. CCL4-neutralizing antibody effectively blocked macrophage-induced prostate tumorigenic signaling and targeting AR via an AR-degradation enhancer, ASC-J9, reduced CCL4 expression, and xenografted tumor growth in vivo. Importantly, CCL4 upregulation was associated with increased Snail expression and downregulation of p53/PTEN in high-grade PIN and prostate cancer. Together, our results identify the AR-CCL4-STAT3 axis as key regulators during prostate tumor initiation and highlight the important roles of infiltrating macrophages and inflammatory cytokines for the prostate tumorigenesis.
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PMID:Infiltrating macrophages promote prostate tumorigenesis via modulating androgen receptor-mediated CCL4-STAT3 signaling. 2387 90

Normal cells enter a senescent state upon aberrant oncogenic signals and this response inhibits tumor initiation and progression. It is now well admitted that intracellular and membrane localized oncogenes can illicit oncogene induced senescence. However, the effect of mitogenic growth factor on cellular senescence is so far largely unknown. Here we show that normal human dermal fibroblasts display a complex response to Platelet derived growth factor B (PDGFB) expression. Indeed, PDGFB expression induces, in the same cell population, both senescence and cellular transformation. Remarkably both populations are sustained with passages suggesting that transformed cells eventually enter a senescent state. This senescence state is p53 dependent as inhibiting the p53 pathway blocks the ability of PDGFB to induce senescence and results in strong cellular transformation increase upon PDGFB expression. The relevance of these observations is supported by the fact that human dermatofibrosarcoma protuberans, skin tumors arising from constitutive PDGFB production with little aggressiveness, also display some senescence hallmarks. Together these data support the view that PDGFB, a mitogenic growth factor, has a limited ability to induce senescence. We propose that this low level of senescence might decrease the transforming ability of this factor without totally abolishing it.
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PMID:Platelet-derived growth factor B induces senescence and transformation in normal human fibroblasts. 2393 86

The Notch pathway has been implicated in a number of malignancies with different roles that are cell- and tissue-type dependent. Notch1 is a putative oncogene in non-small cell lung cancer (NSCLC) and activation of the pathway represents a negative prognostic factor. To establish the role of Notch1 in lung adenocarcinoma, we directly assessed its requirement in Kras-induced tumorigenesis in vivo using an autochthonous model of lung adenocarcinoma with concomitant expression of oncogenic Kras and deletion of Notch1. We found that Notch1 function is required for tumor initiation via suppression of p53-mediated apoptosis through the regulation of p53 stability. These findings implicate Notch1 as a critical effector in Kras-driven lung adenocarcinoma and as a regulator of p53 at a posttranslational level. Moreover, our study provides new insights to explain, at a molecular level, the correlation between Notch1 activity and poor prognosis in patients with NSCLC carrying wild-type p53. This information is critical for design and implementation of new therapeutic strategies in this cohort of patients representing 50% of NSCLC cases.
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PMID:Notch1 is required for Kras-induced lung adenocarcinoma and controls tumor cell survival via p53. 2394 99

Phase II detoxification enzymes are known to play essential roles in the detoxification and elimination of activated carcinogens during tumor initiation, while apoptosis is one of the most important chemopreventive targets for inhibiting tumor promotion in cancer. In this study, we investigated the cancer chemopreventive activity of two plant extracts, the ethanolic extract of Adenocaulon himalaicum (AHE) and the butanolic fraction of AHE (AHB). Both, the AHE and AHB induced NQO1 activity and had relatively high chemoprevention indices (CI=12.4). The AHE and AHB were associated with increased NQO1 and HO-1 mRNA levels via Nrf2-ARE pathway activation. In addition, the AHB increased CYP1A1 activity through AhR-XRE pathway activation. We also found that the AHE and AHB induced apoptosis, as evidenced by phosphatidylserine externalization, an increase in the sub-G0/G1 content, chromatin condensation, poly(ADP-ribose) polymerase cleavage, and p53 induction. These data suggest that AHE and AHB act as bifunctional inducers and that their chemopreventive effects result from the biphasic induction of phase II detoxification enzymes and apoptosis. Therefore, these results suggest that A. himalaicum plant extracts have potential for use as chemopreventive agents for the prevention and/or treatment of human cancers.
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PMID:Bifunctional chemopreventive effects of Adenocaulon himalaicum through induction of detoxification enzymes and apoptosis. 2395 54

John Cunningham virus (JCV) infects chronically human populations worldwide and probably might confer a higher risk for colorectal cancer (CRC). The prevalence of JCV DNA has been determined in normal colon mucosa and compared it with different degrees of colorectal lesions, as well as viral presence in the urine of the individuals in the study. JCV DNA was detected by a nested-PCR approach targeting the JCV small-t antigen in 100 healthy controls, and 100 patients undergoing biopsy for diagnosis of colorectal disorders. JCV DNA was detected in 40% of normal mucosa from controls and patients. JCV DNA presence in urine was also similar in controls and patients (37-41% range). JCV DNA detection in normal mucosa and urine reflects the infected population in Portugal. However, in cases with colorectal tumor lesions, JCV DNA was detected in 90% cases, independently of histological type or grade, and this increase was significantly higher with respect to its normal surrounding mucosa. This higher detection of JCV DNA in tumor lesions with respect to its own normal mucosa suggested that a selection for virus containing cells has occurred at some early stage in tumor initiation or progression. JCV may have a specific tropism for colon epithelial cells with some inherent predisposition that makes them more prone to oncogenic transformation, with selection of infected cells. Several p53 polymorphisms in intron 2, common to both groups, were more frequently detected in colorectal pathology cases. A novel p53 mutation in the 3' untranslated region (exon 11) was identified in 10 patients.
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PMID:Human JC polyomavirus in normal colorectal mucosa, hyperplastic polyps, sporadic adenomas, and adenocarcinomas in Portugal. 2400 84


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