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1.
Int J Cancer ; 137(10): 2296-309, 2015 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-25991553

RESUMO

Cellular transformation is initiated by the activation of oncogenes and a closely associated developmental reprogramming of the epigenetic landscape. Transcription factors, regulators of chromatin states and microRNAs influence cell fates in development and stabilize the phenotypes of normal, differentiated cells and of cancer cells. The miR-302/367 cluster, predominantly expressed in human embryonic stem cells (hESs), can promote the cellular reprogramming of human and mouse cells and contribute to the generation of iPSC. We have used the epigenetic reprogramming potential of the miR-302/367 cluster to "de-program" tumor cells, that is, hift their gene expression pattern towards an alternative program associated with more benign cellular phenotypes. Induction of the miR-302/367 cluster in extensively mutated U87MG glioblastoma cells drastically suppressed the expression of transformation related proteins, for example, the reprogramming factors OCT3/4, SOX2, KLF4 and c-MYC, and the transcription factors POU3F2, SALL2 and OLIG2, required for the maintenance of glioblastoma stem-like tumor propagating cells. It also diminished PI3K/AKT and STAT3 signaling, impeded colony formation in soft agar and cell migration and suppressed pro-inflammatory cytokine secretion. At the same time, the miR-302/367 cluster restored the expression of neuronal markers of differentiation. Most notably, miR-302/367 cluster expressing cells lose their ability to form tumors and to establish liver metastasis in nude mice. The induction of the miR-302/367 cluster in U87MG glioblastoma cells suppresses the expression of multiple transformation related genes, abolishes the tumor and metastasis formation potential of these cells and can potentially become a new approach for cancer therapy.


Assuntos
Neoplasias Encefálicas/genética , Transformação Celular Neoplásica/patologia , Citocinas/metabolismo , Glioblastoma/genética , MicroRNAs/genética , Fatores de Transcrição/metabolismo , Animais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Movimento Celular , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Reprogramação Celular , Regulação Neoplásica da Expressão Gênica , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Fator 4 Semelhante a Kruppel , Camundongos , Camundongos Nus , Transplante de Neoplasias
2.
Cancers (Basel) ; 7(1): 503-37, 2015 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-25809097

RESUMO

Signal transducers and activators of transcription (Stats) play central roles in the conversion of extracellular signals, e.g., cytokines, hormones and growth factors, into tissue and cell type specific gene expression patterns. In normal cells, their signaling potential is strictly limited in extent and duration. The persistent activation of Stat3 or Stat5 is found in many human tumor cells and contributes to their growth and survival. Stat5 activation plays a pivotal role in nearly all hematological malignancies and occurs downstream of oncogenic kinases, e.g., Bcr-Abl in chronic myeloid leukemias (CML) and Jak2(V617F) in other myeloproliferative diseases (MPD). We defined the mechanisms through which Stat5 affects growth and survival of K562 cells, representative of Bcr-Abl positive CML, and HEL cells, representative for Jak2(V617F) positive acute erythroid leukemia. In our experiments we suppressed the protein expression levels of Stat5a and Stat5b through shRNA mediated downregulation and demonstrated the dependence of cell survival on the presence of Stat5. Alternatively, we interfered with the functional capacities of the Stat5 protein through the interaction with a Stat5 specific peptide ligand. This ligand is a Stat5 specific peptide aptamer construct which comprises a 12mer peptide integrated into a modified thioredoxin scaffold, S5-DBD-PA. The peptide sequence specifically recognizes the DNA binding domain (DBD) of Stat5. Complex formation of S5-DBD-PA with Stat5 causes a strong reduction of P-Stat5 in the nuclear fraction of Bcr-Abl-transformed K562 cells and a suppression of Stat5 target genes. Distinct Stat5 mediated survival mechanisms were detected in K562 and Jak2(V617F)-transformed HEL cells. Stat5 is activated in the nuclear and cytosolic compartments of K562 cells and the S5-DBD-PA inhibitor most likely affects the viability of Bcr-Abl+ K562 cells through the inhibition of canonical Stat5 induced target gene transcription. In HEL cells, Stat5 is predominantly present in the cytoplasm and the survival of the Jak2(V617F)+ HEL cells is impeded through the inhibition of the cytoplasmic functions of Stat5.

3.
Anal Biochem ; 466: 83-8, 2014 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-25172132

RESUMO

The presence of endotoxins in preparations of recombinantly produced therapeutic proteins poses serious problems for patients. Endotoxins can cause fever, respiratory distress syndromes, intravascular coagulation, or endotoxic shock. A number of methods have been devised to remove endotoxins from protein preparations using separation procedures based on molecular mass or charge properties. Most of the methods are limited in their endotoxin removal capacities and lack general applicability. We are describing a biotechnological approach for endotoxin removal. This strategy exploits the observation that endotoxins form micelles that expose negative charges on their surface, leading to preferential binding of endotoxins to cationic surfaces, allowing the separation from their resident protein. Endotoxins exhibit high affinity to stretches of histidines, which are widely used tools to facilitate the purification of recombinant proteins. They bind to nickel ions and are the basis for protein purification from cellular extracts by immobilized metal affinity chromatography. We show that the thrombin-mediated cleavage of two histidine tags from the purified recombinant protein and the adsorption of these histidine tags and their associated endotoxins to a nickel affinity column result in an appreciable depletion of the endotoxins in the purified protein fraction.


Assuntos
Química Farmacêutica/métodos , Endotoxinas/isolamento & purificação , Histidina/química , Proteínas Recombinantes/química , Animais , Linhagem Celular , Células Cultivadas , Química Farmacêutica/normas , Química Farmacêutica/tendências , Histidina/metabolismo , Humanos , Lipopolissacarídeos/isolamento & purificação , Camundongos , Ligação Proteica , Proteínas Recombinantes/metabolismo
4.
Pharmaceuticals (Basel) ; 6(8): 960-87, 2013 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-24276378

RESUMO

The signal transducer and activator of transcription Stat5 is transiently activated by growth factor and cytokine signals in normal cells, but its persistent activation has been observed in a wide range of human tumors. Aberrant Stat5 activity was initially observed in leukemias, but subsequently also found in carcinomas. We investigated the importance of Stat5 in human tumor cell lines. shRNA mediated downregulation of Stat5 revealed the dependence of prostate and breast cancer cells on the expression of this transcription factor. We extended these inhibition studies and derived a peptide aptamer (PA) ligand, which directly interacts with the DNA-binding domain of Stat5 in a yeast-two-hybrid screen. The Stat5 specific PA sequence is embedded in a thioredoxin (hTRX) scaffold protein. The resulting recombinant protein S5-DBD-PA was expressed in bacteria, purified and introduced into tumor cells by protein transduction. Alternatively, S5-DBD-PA was expressed in the tumor cells after infection with a S5-DBD-PA encoding gene transfer vector. Both strategies impaired the DNA-binding ability of Stat5, suppressed Stat5 dependent transactivation and caused its intracellular degradation. Our experiments describe a peptide based inhibitor of Stat5 protein activity which can serve as a lead for the development of a clinically useful compound for cancer treatment.

5.
Curr Signal Transduct Ther ; 8(3): 193-202, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25045345

RESUMO

The emergence of low molecular weight kinase inhibitors as "targeted" drugs has led to remarkable advances in the treatment of cancer patients. The clinical benefits of these tumor therapies, however, vary widely in patient populations and with duration of treatment. Intrinsic and acquired resistance against such drugs limits their efficacy. In addition to the well studied mechanisms of resistance based upon drug transport and metabolism, genetic alterations in drug target structures and the activation of compensatory cell signaling have received recent attention. Adaptive responses can be triggered which counteract the initial dependence of tumor cells upon a particular signaling molecule and allow only a transient inhibition of tumor cell growth. These compensating signaling mechanisms are often based upon the relief of repression of regulatory feedback loops. They might involve cell autonomous, intracellular events or they can be mediated via the secretion of growth factor receptor ligands into the tumor microenvironment and signal induction in an auto- or paracrine fashion. The transcription factors Stat3 and Stat5 mediate the biological functions of cytokines, interleukins and growth factors and can be considered as endpoints of multiple signaling pathways. In normal cells this activation is transient and the Stat molecules return to their non-phosphorylated state within a short time period. In tumor cells the balance between activating and de-activating signals is disturbed resulting in the persistent activation of Stat3 or Stat5. The constant activation of Stat3 induces the expression of target genes, which cause the proliferation and survival of cancer cells, as well as their migration and invasive behavior. Activating components of the Jak-Stat pathway have been recognized as potentially valuable drug targets and important principles of compensatory signaling circuit induction during targeted drug treatment have been discovered in the context of kinase inhibition studies in HNSCC cells [1]. The treatment of HNSCC with a specific inhibitor of c-Src, initially resulted in reduced Stat3 and Stat5 activation and subsequently an arrest of cell proliferation and increased apoptosis. However, the inhibition of c-Src only caused a persistent inhibition of Stat5, whereas the inhibition of Stat3 was only transient. The activation of Stat3 was restored within a short time period in the presence of the c-Src inhibitor. This process is mediated through the suppression of P-Stat5 activity and the decrease in the expression of the Stat5 dependent target gene SOCS2, a negative regulator of Jak2. Jak2 activity is enhanced upon SOCS2 downregulation and causes the reactivation of Stat3. A similar observation has been made upon inhibition of Bmx, bone marrow kinase x-linked, activated in the murine glioma cell lines Tu-2449 and Tu-9648. Its inhibition resulted in a transient decrease of P-Stat3 and the induction of a compensatory Stat3 activation mechanism, possibly through the relief of negative feedback inhibition and Jak2 activation. These observations indicate that the inhibition of a single tyrosine kinase might not be sufficient to induce lasting therapeutic effects in cancer patients. Compensatory kinases and pathways might become activated and maintain the growth and survival of tumor cells. The definition of these escape pathways and their preemptive inhibition will suggest effective new combination therapies for cancer.

6.
J Cancer Res Clin Oncol ; 138(7): 1205-20, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22426960

RESUMO

BACKGROUND: Proteins involved in the aberrant regulation of signaling pathways and their downstream effectors are promising targets for cancer therapy. Survivin is an anti-apoptotic and cell cycle-promoting protein, which is consistently overexpressed in cancer cells. In normal cells, its expression is tightly controlled by signaling pathways and their associated transcriptional activators and repressors. In cancer cells, its expression is enhanced as a consequence of oncogenic signaling. We investigated the potential of a novel, peptide-based survivin inhibitor in breast cancer (SK-BR-3, MDA-MB-468) and glioblastoma (Tu9648) cells. These cells express high levels of survivin. MATERIALS AND METHODS: We downregulated survivin expression in tumor cells with a lentiviral gene transfer vector encoding a specific shRNA and a recombinant fusion protein, rSip, comprising the FTH1-derived survivin interaction domain, the human thioredoxin and a protein transduction domain. RESULTS: Downregulation of survivin expression decreased the growth and viability of tumor cells in culture and reduced growth of the cancer cells upon transplantation into immunodeficient mice. rSip selectively targets the anti-apoptotic function of survivin and causes tumor cell death. Non-transformed NIH/3T3 and MCF10A cells remain unaffected. CONCLUSIONS: rSip provides a lead structure for the development of drugs targeting the tumor cell "addiction protein" survivin.


Assuntos
Antineoplásicos/uso terapêutico , Ferritinas/genética , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Proteínas Recombinantes de Fusão/uso terapêutico , Células 3T3 , Animais , Linhagem Celular Tumoral , Proliferação de Células , Regulação para Baixo , Feminino , Ferritinas/metabolismo , Humanos , Proteínas Inibidoras de Apoptose/genética , Proteínas Inibidoras de Apoptose/metabolismo , Camundongos , Oxirredutases , Proteínas Recombinantes de Fusão/genética , Transdução de Sinais/genética , Survivina , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Horm Mol Biol Clin Investig ; 10(2): 255-63, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25436682

RESUMO

Abstract Deregulation of signal transducer and activator of transcription 3 (Stat3) is attracting attentions in neurological disorders of elderly populations, e.g., Stat3 is inactivated in hippocampal neurons of Alzheimer's disease (AD) brains, whereas it is often constitutively activated in glioblastoma multiforme (GBM), correlating with poor prognosis. Stat3-inhibiting drugs have been intensively developed for chemotherapy based on the fact that GBM, in many cases, are "addicted" to Stat3 activation. Stat3 inhibitors, however, potentially have unfavorable side effects on postmitotic neurons, normal permanent residents in the central nervous system. It is, therefore, of great importance to address detailed cellular responses of neural lineage cells including normal neurons, astrocytes, and neuronal/glial cancer cell lines to several classes of Stat3 inhibitors focusing on their effective concentrations. Here, we picked up five human and mouse cancer cell lines (Neuro-2a and SH-SY5Y neuroblastoma cell lines and Tu-9648, U-87MG, and U-373MG glioblastoma cell lines) and treated with various Stat3 inhibitors. Among them, Stattic, FLLL31, and resveratrol potently suppressed P-Stat3 and cell viability in all the tested cell lines. Stat3 knockdown or expression of dominant-negative Stat3 further sensitized cells to the inhibitors. Expression of familial AD-related mutant amyloid precursor protein sensitized neuronal cells, not glial cells, to Stat3 inhibitors by reducing P-Stat3 levels. Primary neurons and astrocytes also responded to Stat3 inhibitors with similar sensitivities to those observed in cancer cell lines. Thus, Stat3 inhibitors should be carefully targeted to GBM cells to avoid potential neurotoxicity leading to AD-like neuropsychiatric dysfunctions.

8.
Horm Mol Biol Clin Investig ; 10(2): 265-72, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25436683

RESUMO

Abstract Signal transducer and activator of transcription 3 (Stat3) assumes central functions in the regulation of apoptosis, proliferation, angiogenesis, and immune responses in normal cells. It also plays crucial roles in inflammatory and malignant diseases and in the cellular communication in the tissue microenvironment. Signaling interactions among normal endothelial cells, immune cells, and tumor cells, mediated by the release of cytokines, chemokines, and growth factors, often result in the activation of Stat3 and promotion of cancer cell proliferation, invasion, angiogenesis, and immune evasion. Stat3 also causes the differentiation and activation of T helper 17 (Th17) cells, which is involved, e.g., in psoriasis, an inflammatory autoimmune disease of the skin. Here, we describe molecular characteristics of a mouse model triggered by the treatment of mouse skin with the immune modulator imiquimod. The application of this compound causes the local release of proinflammatory cytokines and symptoms that resemble human psoriasis. We show that this process is accompanied by strong Stat3 activation. We also investigated the effects of a membrane-permeable, peptide-based Stat3 inhibitor, recombinant Stat3-specific peptide aptamer (rS3-PA). This molecule specifically interacts with Stat3 and prevents its transactivation potential in cultured cells. rS3-PA is able to penetrate the skin, enter cells, and reduce the level of activated Stat3. The topical applications of rS3-PA to the skin could thus possibly become useful in the treatment of inflammatory skin diseases and skin cancer.

9.
Horm Mol Biol Clin Investig ; 10(2): 273-9, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25436684

RESUMO

Abstract Cytotoxic agents, alone or in combination, are being used in the treatment of colorectal cancer. Despite progress in the therapeutic regimes, this common malignancy is still the cause of considerable morbidity and mortality, and further improvements are required. Cancer cells often exhibit intrinsic resistance against chemotherapeutic agents or they develop resistance over the time of treatment. Several mechanisms have been made responsible, e.g., drugs may fail to reach tumor cells or drugs may fail to elicit cytotoxicity. The molecular characterization of drug resistance in cancer cells may lead to strategies to overcome it and enhance the sensitivity to chemotherapy. Irinotecan is one of the main treatments of colorectal cancer; it is converted into its active metabolite SN38 and acts as a topoisomerase I inhibitor. Inhibition of this enzyme prevents DNA relegation following uncoiling. Irinotecan has been used as a chemotherapeutic agent either as a single agent or in combination with 5-fluorouracil and targeted therapies directed against the epidermal growth factor receptor, such as cetuximab. The transcription factor signal transducer and activator of transcription 3 (Stat3) is a member of the signal transducer and activator of transcription protein family. Its persistent activation is found in tumor cells and has been associated with drug and radiation resistance. The treatment of colorectal cancer cells with irinotecan leads to senescence or apoptosis following DNA double-strand break induction. This process is impaired by the activation of Stat3. We have derived a Stat3 specific peptide aptamer [recombinant Stat3 inhibitory peptide aptamer (rS3-PA)] that recognizes the dimerization domain of Stat3 and effectively inhibits its function. The delivery of rS3-PA into colon cancer cells and the resulting inhibition of Stat3 strongly enhanced the cytotoxic action of SN38. These data show that the targeted inhibition of Stat3 decreases drug resistance and enhances SN38-mediated cell death. The combination of these agents has a potent antitumor effect and could become beneficial for the treatment of patients with colorectal cancer.

10.
JAKSTAT ; 1(1): 44-54, 2012 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-24058750

RESUMO

Cancer cells are characterized by the aberrant activation of signaling pathways governing proliferation, survival, angiogenesis, migration and immune evasion. These processes are partially regulated by the transcription factor STAT3. This factor is inappropriately activated in diverse tumor types. Since tumor cells can become dependent on its persistent activation, STAT3 is a favorable drug target. Here, we describe the functional characterization of the recombinant STAT3 inhibitor, rS3-PA. This inhibitor is based on a 20 amino acid peptide which specifically interacts with the dimerization domain of STAT3. It is integrated into a thioredoxin scaffold and fused to a protein transduction domain. Protein gel blot and immunofluorescence analyses showed that rS3-PA is efficiently taken up by cells via an endocytosis independent mechanism. Intracellularly, it reduces the phosphorylation of STAT3 and enhances its degradation. This leads to the downregulation of STAT3 target gene expression on the mRNA and protein levels. Subsequently, tumor cell proliferation, survival and migration and the induction of angiogenesis are inhibited. In contrast, normal cells remain unaffected. Systemic administration of rS3-PA at doses of 7.5 mg/kg reduced P-STAT3 levels and significantly inhibited tumor growth up to 35% in a glioblastoma xenograft mouse model.

11.
Horm Mol Biol Clin Investig ; 5(1): 1-9, 2011 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-25961238

RESUMO

We are characterizing peptides which are able to interact with functional domains of oncoproteins and thus inhibit their activity. The yeast two-hybrid system was used to derive a peptide sequence which specifically interacts with the dimerization domain of the transcription factor Stat3. The activated form of Stat3 is required for the survival of many transformed cells and Stat3 inhibition can cause tumor cell death. The genetic selection of specific peptide sequences from random peptide libraries requires the integration into a scaffold protein and the expression in yeast cells. The scaffold protein, a variant of the human thioredoxin protein, has previously been optimized and also allows for effective bacterial expression of the recombinant protein and the cellular uptake of the purified, recombinant protein. We investigated the contributions of the scaffold protein to the inhibitory properties of rS3-PA. For this purpose we compared rS3-PA in which the ligand peptide is embedded within the thioredoxin scaffold protein with a minimal Stat3-interacting peptide sequence. sS3-P45 is a synthetic peptide of 45 amino acids in length and consists only of the Stat3-binding sequence of 20 amino acids, a protein transduction domain (PTD) and a Flag-tag. Both, the recombinant rS3-PA of 19.3 kDa and the synthetic sS3-P45 of 5.1 kDa, were taken up into the cytoplasm of cells by the PTD-mediated transduction process, inhibited Stat3 target gene expression and caused the death of Stat3-dependent tumor cells. Stat3-independent normal cells were unaffected. rS3-PA effectively inhibited Stat3 function at 2 µM, however, sS3-P45 was required at a concentration of 100 µM to exert the same effects. The more potent action of rS3-PA is most probably due to a conformational stabilization of the Stat3-interacting peptide in the context of the scaffold protein.

12.
Mol Cancer Res ; 8(4): 539-53, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20371673

RESUMO

Signaling components, which confer an "addiction" phenotype on cancer cells, represent promising drug targets. The transcription factor signal transducers and activators of transcription 3 (STAT3) is constitutively activated in many different types of tumor cells and its activity is indispensible in a large fraction. We found that the expression of the endogenous inhibitor of STAT3, protein inhibitor of activated STAT3 (PIAS3), positively correlates with STAT3 activation in normal cells. This suggests that PIAS3 controls the extent and the duration of STAT3 activity in normal cells and thus prevents its oncogenic function. In cancer cells, however, the expression of PIAS3 is posttranscriptionally suppressed, possibly enhancing the oncogenic effects of activated STAT3. We delimited the interacting domains of STAT3 and PIAS3 and identified a short fragment of the COOH-terminal acidic region of PIAS3, which binds strongly to the coiled-coil domain of STAT3. This PIAS3 fragment was used to derive the recombinant STAT3-specific inhibitor rPP-C8. The addition of a protein transduction domain allowed the efficient internalization of rPP-C8 into cancer cells. This resulted in the suppression of STAT3 target gene expression, in the inhibition of migration and proliferation, and in the induction of apoptosis at low concentrations [half maximal effective concentration (EC(50)), <3 micromol/L]. rPP-C8 did not affect normal fibroblasts and represents an interesting lead for the development of novel cancer drugs targeting the coiled-coil domain of STAT3.


Assuntos
Terapia Genética/métodos , Chaperonas Moleculares/genética , Neoplasias/terapia , Peptídeos/genética , Proteínas Inibidoras de STAT Ativados/genética , Proteínas Recombinantes/genética , Fator de Transcrição STAT3/genética , Animais , Morte Celular/genética , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular/genética , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Células Cultivadas , Humanos , Camundongos , Chaperonas Moleculares/química , Chaperonas Moleculares/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Peptídeos/síntese química , Ligação Proteica/genética , Proteínas Inibidoras de STAT Ativados/química , Proteínas Inibidoras de STAT Ativados/metabolismo , Estrutura Terciária de Proteína/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/genética , Transdução Genética/métodos , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
13.
Mol Cancer Res ; 6(2): 267-81, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18314488

RESUMO

Signal transduction events often involve the assembly of protein complexes dependent on modular interactions. The inappropriate assembly of modular components plays a role in oncogenic transformation and can be exploited for therapeutic purposes. Selected peptides embedded in the context of a scaffold protein can serve as competitive inhibitors of intracellular protein functions in cancer cells. Therapeutic application depends on binding specificities and affinities, as well as on the production and purification characteristics of the peptide aptamers and their delivery into cells. We carried out experiments to improve the properties of the scaffold. We found that the commonly used bacterial thioredoxin scaffold is suboptimal for therapeutic purposes because it aggregates during purification and is most likely immunogenic in humans. We compared the properties of peptide aptamers embedded in three alternative scaffold structures: a coiled-coil stem-loop structure, a dimerization domain, and human thioredoxin (hTrx). We found that only the hTrx molecule can be efficiently produced in bacteria and purified with high yield. We removed five internal cysteines of hTrx to circumvent aggregation during purification, which is a prerequisite for efficient transduction. Insertion of our previously characterized peptide aptamers [e.g., specifically binding signal transducer and activator of transcription 3 (Stat3)] into the modified hTrx scaffold retained their target binding properties. Addition of a protein transduction domain, consisting of nine arginines, results in a fusion protein, which is taken up by cultured cells. We show that treatment of glioblastoma cells, expressing constitutively activated Stat3, with the purified peptide aptamers strongly inhibits Stat3 signaling, causing cell growth arrest and inducing apoptosis.


Assuntos
Aptâmeros de Peptídeos/metabolismo , Espaço Intracelular/metabolismo , Proteínas Recombinantes/metabolismo , Sequência de Aminoácidos , Animais , Apoptose , Aptâmeros de Peptídeos/química , Aptâmeros de Peptídeos/isolamento & purificação , Sequência de Bases , Linhagem Celular Tumoral , Proliferação de Células , Cisteína , Escherichia coli , Glioblastoma/patologia , Humanos , Camundongos , Dados de Sequência Molecular , Células NIH 3T3 , Estrutura Quaternária de Proteína , Proteínas Recombinantes/isolamento & purificação , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Tiorredoxinas/química , Tiorredoxinas/genética , Tiorredoxinas/metabolismo , Transdução Genética
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