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)

Hypoxia inducible factor 1 (HIF-1) is a key player in cancer progression and an attractive target for cancer therapy. Several small molecule inhibitors of HIF-1alpha also induce a DNA damage response. However, whether or not DNA damage is required for or associated with the inhibition of HIF-1alpha protein accumulation is poorly understood. In this report we investigated the effects of distinct DNA damaging conditions on the hypoxic induction of HIF-1alpha protein in cancer cell lines. We demonstrate that in addition to topotecan (TPT), a known inhibitor of HIF-1alpha, UVC, but not other DNA damaging agents (cisplatin, ionizing radiation and doxorubicin), inhibited HIF-1alpha protein accumulation in a dose-dependent, p53-independent fashion. Low doses UVC decreased HIF-1alpha translation without affecting global protein synthesis. Inhibition of HIF-1alpha by UVC required ongoing RNA transcription, but not DNA replication. Moreover, a functional ATR was required for the activation of DNA damage-dependent responses by both UVC and TPT, but was dispensable for the inhibition of HIF-1alpha protein. Notably, unlike TPT, inhibition of HIF-1alpha protein by UVC did not require topoisomerase I, suggesting a similar yet distinct mode of action. Our data reveal that UVC is a novel signal associated with inhibition of HIF-1alpha protein accumulation, and they uncouple the DNA damage-dependent signaling pathway exerted by UVC and TPT from HIF-1alpha inhibition.
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PMID:UVC inhibits HIF-1alpha protein translation by a DNA damage- and topoisomerase I-independent pathway. 1749 31

Vascular Endothelial Growth Factor (VEGF) and its transcriptional regulator Hypoxia-inducible Factor 1 (HIF-1) play an important role in the process of angiogenesis in many types of cancer, including ovarian cancer. We have examined whether the DNA-damaging drugs cisplatin and doxorubicin and the microtubule inhibitors docetaxel and paclitaxel can affect VEGF expression and HIF-1 activity in three human ovarian cancer cell lines. We demonstrate that cisplatin and doxorubicin abolish hypoxia-induced VEGF mRNA expression in all cell lines, while basal VEGF mRNA expression was also downregulated. Transient transfection with a HIF-1-responsive luciferase construct indicated that cisplatin and doxorubicin inhibited hypoxic activation of HIF-1. Cisplatin repressed HIF-1alpha protein expression in all cell lines. Stimulation of HIF-1alpha protein degradation by cisplatin was observed in the only cell line expressing wild-type p53. Cisplatin also inhibited the synthesis of HIF-1alpha protein for which p53 was dispensable. Interestingly, cisplatin strongly reduced the protein levels of the HIF-1 coactivators p300 and CREB-binding protein (CBP) under hypoxia in all cell lines. Although doxorubicin inhibited hypoxic activation of HIF-1, this drug had no significant effect on the expression levels of HIF-1alpha and hypoxic expression of p300 and CBP was only weakly reduced. Docetaxel and paclitaxel did neither influence VEGF expression nor hypoxia-induced HIF-1 activity. In total, our findings indicate that cisplatin and doxorubicin can repress hypoxic induction of VEGF expression by inhibiting HIF-1 through different mechanisms. This knowledge may be useful for future treatment schedules including agents that target the HIF-1 signalling pathway.
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PMID:Cisplatin and doxorubicin repress Vascular Endothelial Growth Factor expression and differentially down-regulate Hypoxia-inducible Factor I activity in human ovarian cancer cells. 1749 66

With our growing understanding of the pathways involved in cell proliferation and signaling, targeted therapies, in the treatment of cancer are entering the clinical arena. New and emerging targets are proteins involved in DNA repair pathways. Inhibition of various proteins in the DNA repair pathways sensitizes cancer cells to DNA damaging agents such as chemotherapy and/or radiation. We study the apurinic endonuclease 1/redox factor-1 (Ape1/Ref-1) and believe that its crucial function in DNA repair and reduction-oxidation or redox signaling make it an excellent target for sensitizing tumor cells to chemotherapy. Ape1/Ref-1 is an essential enzyme in the base excision repair (BER) pathway which is responsible for the repair of DNA caused by oxidative and alkylation damage. As importantly, Ape1/Ref-1 also functions as a redox factor maintaining transcription factors in an active reduced state. Ape1/Ref-1 stimulates the DNA binding activity of numerous transcription factors that are involved in cancer promotion and progression such as AP-1 (Fos/Jun), NFkappaB, HIF-1alpha, CREB, p53 and others. We will discuss what is known regarding the pharmacological targeting of the DNA repair activity, as well as the redox activity of Ape1/Ref-1, and explore the budding clinical utility of inhibition of either of these functions in cancer treatment. A brief discussion of the effect of polymorphisms in its DNA sequence is included because of Ape1/Ref-1's importance to maintenance and integrity of the genome. Experimental modification of Ape1/Ref-1 activity changes the response of cells and of organisms to DNA damaging agents, suggesting that Ape1/Ref-1 may also be a productive target of chemoprevention. In this review, we will provide an overview of Ape1/Ref-1's activities and explore the potential of this protein as a target in cancer treatment as well as its role in chemoprevention.
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PMID:The DNA base excision repair protein Ape1/Ref-1 as a therapeutic and chemopreventive target. 1756 Jun 42

Hypoxia-inducible factor 1 (HIF-1) is a ubiquitously expressed transcriptional regulator involved in induction of numerous genes associated with angiogenesis and tumor growth. Kaposi's sarcoma, associated with increased angiogenesis, is a highly vascularized, endothelial cell-derived tumor. Previously, we have shown that the latency-associated nuclear antigen (LANA) encoded by Kaposi's sarcoma-associated herpesvirus (KSHV) targets the HIF-1alpha suppressors von Hippel-Lindau protein and p53 for degradation via its suppressor of cytokine signaling-box motif, which recruits the EC5S ubiquitin complex. Here we further show that HIF-1alpha was aberrantly accumulated in KSHV latently infected primary effusion lymphoma (PEL) cells, as well as HEK293 cells infected with KSHV, and also show that a potential alpha-helical amino-terminal domain of LANA was important for HIF-1alpha nuclear accumulation in normoxic conditions. Moreover, we have now determined that this association was dependent on the residues 46 to 89 of LANA and the oxygen-dependent degradation domain of HIF-1alpha. Introduction of specific small interfering RNA against LANA into PEL cells also resulted in a diminished nuclear accumulation of HIF-1alpha. Therefore, these data show that LANA can function not only as an inhibitor of HIF-1alpha suppressor proteins but can also induce nuclear accumulation of HIF-1alpha during KSHV latent infection.
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PMID:A potential alpha-helix motif in the amino terminus of LANA encoded by Kaposi's sarcoma-associated herpesvirus is critical for nuclear accumulation of HIF-1alpha in normoxia. 1763 30

Heat shock protein 90 (Hsp90) is a molecular chaperone whose association is required for the stability and function of multiple mutated, chimeric and over-expressed signaling proteins that promote the growth and/or survival of cancer cells. Hsp90 client proteins include mutated p53, Bcr-Abl, Raf-1, Akt, HER2/Neu (ErbB2) and HIF-1alpha. Hsp90 inhibitors, by interacting specifically with a single molecular target, cause the destabilization and eventual degradation of Hsp90 client proteins, and the first-in-class Hsp90 inhibitor, 17-allylamino-17 demethoxygeldanamycin (17AAG), is currently in phase II clinical trials. A fraction of Hsp90 has been identified at the cell surface and its presence has recently been shown to correlate with melanoma progression. Inhibition of cell-surface Hsp90 with antibodies or cell-impermeable Hsp90 inhibitors blocks cell motility and invasion in vitro and cancer metastasis in vivo. Thus, cell-surface Hsp90 may play a unique role in tumor metastasis, distinct from but perhaps overlapping with its intracellular function. In addition, because cell-surface Hsp90 may be the point of contact between some viruses and host cells, this pool of the chaperone may play a distinct role in initiation of infectious disease.
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PMID:Extracellular heat shock protein 90: a role for a molecular chaperone in cell motility and cancer metastasis. 1764 79

Due to the prevalence of tumor chemoresistance, the clinical response of advanced non-small cell lung cancer (NSCLC) to chemotherapy is poor. We suppressed tumor resistance to doxorubicin (Dox) in A549 cells, a human NSCLC cell line, both in vitro and in vivo in a lung tumor xenograft model, using a novel adenoviral expression system to deliver an RNA aptamer (A-p50) that specifically inhibits nuclear factor-kappaB (NF-kappaB) activation. By achieving selective, targeted, and early inhibition of NF-kappaB activity, we demonstrate that NF-kappaB plays a critical role in Dox-induced chemoresistance by regulating genes involved in proliferation (Ki-67), response to DNA damage (GADD153), antiapoptosis (Bcl-XL), and pH regulation (CA9). This Dox-induced NF-kappaB activation and subsequent chemoresistance is dependent on expression of p53. We also demonstrate that NF-kappaB promotes angiogenesis in the presence of Dox via the hypoxia-inducible factor-1alpha/vascular endothelial growth factor (HIF-1alpha/VEGF) pathway, revealing a previously unknown mechanism of NSCLC resistance to Dox. These studies provide important insights into the mechanisms of Dox-induced chemoresistance, and they demonstrate a novel, effective, and clinically practical strategy for interfering with these processes.
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PMID:RNA aptamer-targeted inhibition of NF-kappa B suppresses non-small cell lung cancer resistance to doxorubicin. 1791 35

The proteasome controls a plethora of survival factors in all mammalian cells analyzed to date. Therefore, it is puzzling that proteasome inhibitors such as bortezomib can display a preferential toxicity toward malignant cells. In fact, proteasome inhibitors have the salient feature of promoting a dramatic induction of the proapoptotic protein NOXA in a tumor cell-restricted manner. However, the molecular determinants that control this specific regulation of NOXA are unknown. Here, we show that the induction of NOXA by bortezomib is directly dependent on the oncogene c-MYC. This requirement for c-MYC was found in a variety of tumor cell types, in marked contrast with dispensable roles of p53, HIF-1alpha, and E2F-1 (classical proteasomal targets that can regulate NOXA mRNA under stress). Conserved MYC-binding sites identified at the NOXA promoter were validated by ChIP and reporter assays. Down-regulation of the endogenous levels of c-MYC abrogated the induction of NOXA in proteasome-defective tumor cells. Conversely, forced expression of c-MYC enabled normal cells to accumulate NOXA and subsequently activate cell death programs in response to proteasome blockage. c-MYC is itself a proteasomal target whose levels or function are invariably up-regulated during tumor progression. Our data provide an unexpected function of c-MYC in the control of the apoptotic machinery, and reveal a long sought-after oncogenic event conferring sensitivity to proteasome inhibition.
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PMID:Tumor cell-selective regulation of NOXA by c-MYC in response to proteasome inhibition. 1804 11

Hsp90 is an evolutionarily conserved and ubiquitously expressed molecular chaperone that mainly modulates, along with a group of co-chaperones, the general platform of protein folding and prevents the nonspecific aggregation of misfolded or unfolded proteins. In the voluminous Hsp90 clientele, a large variety of important regulatory proteins can be identified, including many whose deregulation may lead to cancer initiation and progression, such as the oncogenic clients pp60(v-src), Bcr-Abl, mutated p53, ErbB2 (Her-2), Akt, Flt3, HIF-1alpha and B-Raf. Therefore, inhibition of Hsp90 function offers the prospect of simultaneously disrupting multiple signaling pathways directly implicated in the development of malignant phenotypes. During the last few years, there has been a major focus on the development of Hsp90 specific inhibitors. This started with the discovery that certain natural products could specifically disrupt Hsp90 chaperone activities. The benzoquinone ansamycin antibiotic geldanamycin and its less toxic derivative 17-AAG have been shown to possess strong anti-proliferative and apoptotic activity in cancer cells, whereas 17-AAG has demonstrated potent anti-tumor activity in several human xenograft models, including breast, prostate and colon cancer. In an effort to overcome difficulties with drug toxicity and solubility, a number of novel bioengineered 17-AAG analogues, such as 17-DMAG and IPI-504, and small-molecule inhibitors, including purine and pyrazole derivatives, have emerged from rational drug design followed by high-throughput screening approaches. 17-AAG was the leader inhibitor to enter and successfully complete phase I clinical trials, thus demonstrating that Hsp90 constitutes a valid drug target for cancer therapy. This review includes information on the current model of ternary interactions between Hsp90, client proteins and a vast array of co-chaperones followed by a list of characteristic inhibitors and ongoing clinical trials reported thus far.
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PMID:Drug-mediated targeted disruption of multiple protein activities through functional inhibition of the Hsp90 chaperone complex. 1822 Jul 46

Extensive research within the last decade has revealed that most chronic illnesses such as cancer, cardiovascular and pulmonary diseases, neurological diseases, diabetes, and autoimmune diseases exhibit dysregulation of multiple cell signaling pathways that have been linked to inflammation. Thus mono-targeted therapies developed for the last two decades for these diseases have proven to be unsafe, ineffective and expensive. Although fruits and vegetables are regarded to have therapeutic potential against chronic illnesses, neither their active component nor the mechanism of action is well understood. Resveratrol (trans-3, 5, 4'-trihydroxystilbene), a component of grapes, berries, peanuts and other traditional medicines, is one such polyphenol that has been shown to mediate its effects through modulation of many different pathways. This stilbene has been shown to bind to numerous cell-signaling molecules such as multi drug resistance protein, topoisomerase II, aromatase, DNA polymerase, estrogen receptors, tubulin and F1-ATPase. Resveratrol has also been shown to activate various transcription factor (e.g; NFkappaB, STAT3, HIF-1alpha, beta-catenin and PPAR-gamma), suppress the expression of antiapoptotic gene products (e.g; Bcl-2, Bcl-X(L), XIAP and survivin), inhibit protein kinases (e.g; src, PI3K, JNK, and AKT), induce antioxidant enzymes (e,g; catalase, superoxide dismutase and hemoxygenase-1), suppress the expression of inflammatory biomarkers (e.g., TNF, COX-2, iNOS, and CRP), inhibit the expression of angiogenic and metastatic gene products (e.g., MMPs, VEGF, cathepsin D, and ICAM-1), and modulate cell cycle regulatory genes (e.g., p53, Rb, PTEN, cyclins and CDKs). Numerous animal studies have demonstrated that this polyphenol holds promise against numerous age-associated diseases including cancer, diabetes, Alzheimer, cardiovascular and pulmonary diseases. In view of these studies, resveratrol's prospects for use in the clinics are rapidly accelerating. Efforts are also underway to improve its activity in vivo through structural modification and reformulation. Our review describes various targets of resveratrol and their therapeutic potential.
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PMID:Resveratrol: a multitargeted agent for age-associated chronic diseases. 1841 53

Therapy targeting hypoxia-inducible factor-1 (HIF-1) to reverse the hypoxia-related drug resistance has received much interest. Despite a close interaction between HIF-1 and p53 and that p53 mutation is seen in >50% of tumors, whether HIF-1 silencing by targeted therapy depends on tumor p53 status remains unknown. Two isogenic fibrosarcoma cells HT1080 (wild-type p53) and HT1080-6TG (mutant p53) were transduced with HIF-1alpha-specific RNAi lentiviral vectors and selected with blasticidin. Real-time PCR and western blot analysis of HIF-1alpha mRNA and protein respectively validated the silencing effects. Cells were first preconditioned under hypoxia (0.5% O(2)) for 4 h and then co-treated with cisplatin for another 24 h. MTT was used for assessment of chemosensitivity to cisplatin. Moreover, annexin V and propidium iodide staining was detected on flow cytometry for analysis of cisplatin-induced apoptosis. Furthermore, changes of some Bcl-2 family members were detected on western blotting. Exposure to hypoxia significantly increased resistance to cisplatin than exposure to normoxia. HIF-1alpha knockdown could reverse hypoxia-related resistance to cisplatin and apoptotic resistance only in HT1080 cells, but had little effect on HT1080-6TG cells. With HIF-1alpha knockdown, Bid expression was higher in HT1080 than in HT1080-6TG under hypoxia. In summary, HIF-1 targeted therapy to reverse hypoxia-related cisplatin resistance depends on normal p53 status. Changes of Bid expression levels under hypoxia might contribute in part to the differential response to HIF-1alpha silencing in cells with different p53 status.
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PMID:Effects of lentivirus-mediated HIF-1alpha knockdown on hypoxia-related cisplatin resistance and their dependence on p53 status in fibrosarcoma cells. 1842 7


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