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1.
Biochem Biophys Res Commun ; 377(4): 1107-12, 2008 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-18983820

RESUMO

Nuclear-Factor-kappaB (NF-kappaBeta can counteract transforming growth factor-beta1 (TGF-beta1)-induced apoptosis in malignant hepatocytes through up-regulation of its downstream genes, such as X-linked inhibitor of apoptosis protein (XIAP). Reports have demonstrated that TGF-beta1 can induce oxidative stress, and c-Jun N-terminal Kinase1 (JNK1) is indispensable for TGF-beta1-induced apoptosis pathway, but the relationship between radical oxygen species (ROS) and the activation of JNKs is still unclear. In the present study, we found that ROS can induce JNK activation in TGF-beta1 mediated apoptosis in hepatocytes. The inhibitors of hydrogen peroxide and superoxide, which were produced by mitochondria under stress, could inhibit the phosphorylation of c-Jun in XIAP knockdown cells. In conclusion, it is the first time to show that both NF-kappaB and antioxidants can counteract TGF-beta1-induced apoptosis in hepatic cell death through JNK1 pathway.


Assuntos
Apoptose , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , NF-kappa B/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fator de Crescimento Transformador beta1/farmacologia , Antioxidantes/farmacologia , Linhagem Celular Tumoral , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , MAP Quinase Quinase 4/antagonistas & inibidores , MAP Quinase Quinase 4/metabolismo , MAP Quinase Quinase Quinases/antagonistas & inibidores , MAP Quinase Quinase Quinases/metabolismo , NF-kappa B/antagonistas & inibidores , Estresse Oxidativo , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo
2.
Mol Cell Biol ; 24(5): 1823-35, 2004 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-14966265

RESUMO

We have identified a novel pathway of ataxia telangiectasia mutated (ATM) and DNA-dependent protein kinase (DNA-PK) signaling that results in nuclear factor kappaB (NF-kappaB) activation and chemoresistance in response to DNA damage. We show that the anthracycline doxorubicin (DOX) and its congener N-benzyladriamycin (AD 288) selectively activate ATM and DNA-PK, respectively. Both ATM and DNA-PK promote sequential activation of the mitogen-activated protein kinase (MAPK)/p90(rsk) signaling cascade in a p53-independent fashion. In turn, p90(rsk) interacts with the IkappaB kinase 2 (IKK-2) catalytic subunit of IKK, thereby inducing NF-kappaB activity and cell survival. Collectively, our findings suggest that distinct members of the phosphatidylinositol kinase family activate a common prosurvival MAPK/IKK/NF-kappaB pathway that opposes the apoptotic response following DNA damage.


Assuntos
Dano ao DNA , Proteínas de Ligação a DNA , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Transdução de Sinais/fisiologia , Animais , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/metabolismo , Proteínas Mutadas de Ataxia Telangiectasia , Proteínas de Ciclo Celular , Sobrevivência Celular , Proteína Quinase Ativada por DNA , Doxorrubicina/análogos & derivados , Doxorrubicina/metabolismo , Ativação Enzimática , Inibidores Enzimáticos/metabolismo , Fibroblastos/citologia , Fibroblastos/metabolismo , Humanos , Quinase I-kappa B , Camundongos , Células NIH 3T3 , Proteínas Nucleares , Subunidades Proteicas/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteínas Supressoras de Tumor
3.
Mol Cancer Res ; 3(7): 403-12, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16046551

RESUMO

Nuclear factor-kappaB (NF-kappaB) plays an important role during liver neoplastic development through transcriptional regulation of prosurvival genes, which then counteract the death-inducing signals elicited by the host immune response. The c-Myc proto-oncogene is frequently deregulated in liver tumors. Furthermore, enforced expression of c-Myc in the liver promotes the development of hepatocellular carcinomas, a process that is accelerated by coexpression with transforming growth factor-alpha (TGF-alpha). TGF-alpha/c-Myc-derived hepatocellular carcinomas display reduced apoptotic levels compared with those of single c-Myc transgenic hepatocellular carcinomas, suggesting that TGF-alpha provides a survival advantage to c-Myc-transformed hepatocytes. Given that TGF-alpha/c-Myc hepatocellular carcinomas display constitutive NF-kappaB activity, here, we have tested the hypothesis that enforced expression of TGF-alpha results in constitutive NF-kappaB activation and enhanced cell survival using TGF-alpha/c-Myc-derived hepatocellular carcinoma cell lines. We show that TGF-alpha induces NF-kappaB through the phosphatidylinositol 3-kinase/Akt axis in these bitransgenic hepatocellular carcinomas. Furthermore, we found that adenovirus-mediated inhibition of NF-kappaB activity impairs the ability of TGF-alpha/c-Myc-derived tumor cells to grow in an anchorage-independent fashion due to sensitization to c-Myc-induced apoptosis. Lastly, we show that NF-kappaB inhibits c-Myc-induced activation of caspase-9 and caspase-3 through up-regulation of the antiapoptotic target genes Bcl-X(L) and X-linked inhibitor of apoptosis (XIAP). Overall, these results underscore a crucial role of NF-kappaB in disabling apoptotic pathways initiated by oncogenic transformation.


Assuntos
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-myc/fisiologia , Fator de Crescimento Transformador alfa/fisiologia , Animais , Apoptose/genética , Northern Blotting , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Caspase 3 , Caspase 9 , Caspases/genética , Caspases/metabolismo , Linhagem Celular Tumoral , Ensaio de Desvio de Mobilidade Eletroforética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Transgênicos , Proteínas Serina-Treonina Quinases , Fator de Transcrição RelA , Regulação para Cima
4.
Cancer Res ; 64(19): 7030-8, 2004 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-15466196

RESUMO

Nuclear factor-kappaB (NF-kappaB) plays a critical role during fetal liver development and hepatic oncogenesis. Here, we have assessed whether NF-kappaB activity is required for murine hepatocellular carcinoma cell survival. We show that adenoviral-mediated inhibition of inhibitor of NF-kappaB kinase-beta (IKK-2) activity in hepatocellular carcinomas derived from transforming growth factor (TGF)-alpha/c-myc bitransgenic mice leads to inhibition of NF-kappaB and promotes tumor necrosis factor (TNF)-alpha-mediated cell death of malignant hepatocytes but not the surrounding peritumorous tissue. Induction of apoptosis is accompanied by inhibition of Bcl-X(L) and XIAP, two pro-survival NF-kappaB target genes. In addition, we have identified the alpha-fetoprotein (AFP) as a novel downstream target of NF-kappaB. We show that repression of IKK-2 activity in hepatocellular carcinomas promotes down-regulation of AFP gene expression. Likewise, genetic disruption of the RelA subunit results in reduced AFP gene expression during embryonic liver development, at a time in which fetal hepatocytes are sensitized to TNF-alpha-mediated cell killing. In this regard, we show that AFP inhibits TNF-alpha-induced cell death of murine hepatocellular carcinomas through association with TNF-alpha and inhibition of TNFRI signaling. Thus, NF-kappaB-mediated regulation of AFP gene expression during liver tumor formation and embryonic development of the liver constitutes a potential novel mechanism used by malignant and fetal hepatocytes to evade immune surveillance.


Assuntos
Hepatócitos/patologia , Neoplasias Hepáticas Experimentais/patologia , Fígado/embriologia , NF-kappa B/fisiologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , alfa-Fetoproteínas/fisiologia , Adenoviridae/genética , Animais , Antígenos CD/fisiologia , Apoptose/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Hepatócitos/metabolismo , Quinase I-kappa B , Fígado/enzimologia , Fígado/fisiologia , Neoplasias Hepáticas Experimentais/enzimologia , Masculino , Camundongos , Camundongos Transgênicos , NF-kappa B/genética , NF-kappa B/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-myc , Receptores do Fator de Necrose Tumoral/fisiologia , Receptores Tipo I de Fatores de Necrose Tumoral , Fator de Crescimento Transformador alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/fisiologia , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X , alfa-Fetoproteínas/genética , alfa-Fetoproteínas/metabolismo , Proteína bcl-X
5.
Oncogene ; 22(3): 412-25, 2003 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-12545162

RESUMO

NF-kappaB has been implicated in the regulation of apoptosis, a key mechanism of normal and malignant growth control. Previously, we demonstrated that inhibition of NF-kappaB activity by TGF-beta1 leads directly to induction of apoptosis of murine B-cell lymphomas and hepatocytes. Thus, we were surprised to determine that NF-kappaB is transiently activated in response to TGF-beta1 treatment. Here we elucidate the mechanism of TGF-beta1-mediated regulation of NF-kappaB and induction of apoptosis in epithelial cells. We report that TGF-beta1 activates IKK kinase, which mediates IkappaB-alpha phosphorylation. In turn, the activation of IKK following TGF-beta1 treatment is mediated by the TAK1 kinase. As a result of NF-kappaB activation, IkappaB-alpha mRNA and protein levels are increased leading to postrepression of NF-kappaB and induction of cell death. Inhibition of NF-kappaB following TGF-beta1 treatment increased AP-1 complex transcriptional activity through sustained c-Jun phosphorylation, thereby potentiating AP-1/SMADs-mediated cell killing. Furthermore, TGF-beta1-mediated upregulation of Smad7 appeared independent of NF-kappaB. In hepatocellular carcinomas of TGF-beta1 or TGF-alpha/c-myc transgenic mice, we observed constitutive activation of NF-kappaB that led to inhibition of JNK signaling. Overall, our data illustrate an autocrine mechanism based on the ability of IKK/NF-kappaB/IkappaB-alpha signaling to negatively regulate NF-kappaB levels thereby permitting TGF-beta1-induced apoptosis through AP-1 activity.


Assuntos
Proteínas de Ligação a DNA/metabolismo , MAP Quinase Quinase Quinases/metabolismo , NF-kappa B/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Transativadores/metabolismo , Fator de Transcrição AP-1/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Células Cultivadas , Proteínas de Ligação a DNA/genética , Ativação Enzimática , Hepatócitos/citologia , Hepatócitos/metabolismo , Quinase I-kappa B , Proteínas I-kappa B/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , MAP Quinase Quinase Quinases/genética , Camundongos , Camundongos Transgênicos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/genética , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Transporte Proteico/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Transdução de Sinais , Proteína Smad7 , Transativadores/genética , Fator de Crescimento Transformador beta/farmacologia , Fator de Crescimento Transformador beta1
6.
Cancer Lett ; 229(2): 157-69, 2005 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-16125305

RESUMO

Hepatocellular carcinoma (HCC) is the third deadliest and fifth most common human cancer worldwide. Hepatitis C virus (HCV) and hepatitis B virus (HBV) infections along with alcohol and aflatoxin B1 intake are widely recognized etiological agents in HCCs. It is anticipated that HCCs will constitute a major health problem in the next two decades because of the rising incidence of HCV infections in the US. The poor survival rate achieved by current surgical procedures and chemotherapy treatment has prompted the scientific community to gain a better understanding of the molecular events involved in hepatocarcinogenesis in order to define new targets for more effective treatment. Recent findings from several laboratories have implicated constitutive activation of the transcription factor NF-kappaB as one of the early key events involved in neoplastic progression of the liver. Data is summarized here from recently published studies illustrating a crucial role of NF-kappaB in bridging the action of growth factors and inflammation to hepatic oncogenesis. Although additional work is needed to fully understand the precise role of NF-kappaB in the regulation of the various transitions of HCC development, these new findings raise the intriguing possibility that pharmacologic inhibition of NF-kappaB in the liver could selectively eradicate malignant liver cells without affecting normal liver homeostasis.


Assuntos
Carcinoma Hepatocelular/etiologia , Transformação Celular Neoplásica/metabolismo , Neoplasias Hepáticas/etiologia , NF-kappa B/metabolismo , Transdução de Sinais/fisiologia , Animais , Carcinoma Hepatocelular/fisiopatologia , Substâncias de Crescimento/metabolismo , Humanos , Inflamação/metabolismo , Neoplasias Hepáticas/fisiopatologia , Infecções Tumorais por Vírus/complicações
7.
Gastroenterology ; 132(5): 1834-51, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17484878

RESUMO

BACKGROUND & AIMS: We recently identified lysophosphatidic acid (LPA) as a potent antiapoptotic agent for the intestinal epithelium. The objective of the present study was to evaluate the effect of octadecenyl thiophosphate (OTP), a novel rationally designed, metabolically stabilized LPA mimic, on radiation-induced apoptosis of intestinal epithelial cells in vitro and in vivo. METHODS: The receptors and signaling pathways activated by OTP were examined in IEC-6 and RH7777 cell lines and wild-type and LPA(1) and LPA(2) knockout mice exposed to different apoptotic stimuli. RESULTS: OTP was more efficacious than LPA in reducing gamma irradiation-, camptothecin-, or tumor necrosis factor alpha/cycloheximide-induced apoptosis and caspase-3-8, and caspase-9 activity in the IEC-6 cell line. In RH7777 cells lacking LPA receptors, OTP selectively protected LPA(2) but not LPA(1) and LPA(3) transfectants. In C57BL/6 and LPA(1) knockout mice exposed to 15 Gy gamma irradiation, orally applied OTP reduced the number of apoptotic bodies and activated caspase-3-positive cells but was ineffective in LPA(2) knockout mice. OTP, with higher efficacy than LPA, enhanced intestinal crypt survival in C57BL/6 mice but was without any effect in LPA(2) knockout mice. Intraperitoneally administered OTP reduced death caused by lethal dose (LD)(100/30) radiation by 50%. CONCLUSIONS: Our data indicate that OTP is a highly effective antiapoptotic agent that engages similar prosurvival pathways to LPA through the LPA(2) receptor subtype.


Assuntos
Apoptose/efeitos da radiação , Mucosa Intestinal/efeitos da radiação , Compostos Organofosforados/farmacologia , Lesões Experimentais por Radiação/prevenção & controle , Receptores de Ácidos Lisofosfatídicos/fisiologia , Administração Oral , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Linhagem Celular , Células Cultivadas , Relação Dose-Resposta a Droga , Feminino , Proteínas de Ligação ao GTP/fisiologia , Raios gama/efeitos adversos , Regulação da Expressão Gênica , Injeções Intraperitoneais , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Quinases Ativadas por Mitógeno/fisiologia , Proteínas do Tecido Nervoso/farmacologia , Compostos Organofosforados/administração & dosagem , Fosfatidilinositol 3-Quinases/fisiologia , Lesões Experimentais por Radiação/metabolismo , Lesões Experimentais por Radiação/patologia , Receptores de Ácidos Lisofosfatídicos/genética , Transdução de Sinais/fisiologia , Fator de Necrose Tumoral alfa/farmacologia
8.
J Biol Chem ; 280(46): 38599-608, 2005 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-16157589

RESUMO

Active NF-kappaB renders malignant hepatocytes refractory to the growth inhibitory and pro-apoptotic properties of transforming growth factorbeta1 (TGF-beta1). NF-kappaB counteracts TGF-beta1-induced apoptosis through up-regulation of downstream target genes, such as XIAP and Bcl-X(L), which in turn inhibit the intrinsic pathway of apoptosis. In addition, induction of NF-kappaB by TGF-beta1 inhibits JNK signaling, thereby attenuating TGF-beta1-induced cell death of normal hepatocytes. However, the mechanism involved in the negative cross-talk between the NF-kappaB and JNK pathways during TGF-beta1 signaling has not been determined. In this study, we have identified the XIAP gene as one of the critical mediators of NF-kappaB-mediated suppression of JNK signaling. We show that NF-kappaB plays a role in the up-regulation of XIAP gene expression in response to TGF-beta1 treatment and forms a TGF-beta1-inducible complex with TAK1. Furthermore, we show that the RING domain of XIAP mediates TAK1 polyubiquitination, which then targets this molecule for proteosomal degradation. Down-regulation of TAK1 protein expression inhibits TGF-beta1-mediated activation of JNK and apoptosis. Conversely, silencing of XIAP promotes persistent JNK activation and potentiates TGF-beta1-induced apoptosis. Collectively, our findings identify a novel mechanism for the regulation of JNK activity by NF-kappaB during TGF-beta1 signaling and raise the possibility that pharmacologic inhibition of the NF-kappaB/XIAP signaling pathway might selectively abolish the pro-oncogenic activity of TGF-beta1 in advanced hepatocellular carcinomas (HCCs) without affecting the pro-apoptotic effects of TGF-beta1 involved in normal liver homeostasis.


Assuntos
MAP Quinase Quinase Quinases/metabolismo , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Ubiquitina/metabolismo , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/fisiologia , Animais , Antracenos/farmacologia , Apoptose , Carcinoma Hepatocelular/metabolismo , Morte Celular , Células Cultivadas , Relação Dose-Resposta a Droga , Regulação para Baixo , Ativação Enzimática , Inibidores Enzimáticos/farmacologia , Inativação Gênica , Glutationa Transferase/metabolismo , Hepatócitos/metabolismo , Humanos , Immunoblotting , Luciferases/metabolismo , MAP Quinase Quinase 4/metabolismo , Masculino , Camundongos , Modelos Biológicos , NF-kappa B/metabolismo , Ligação Proteica , Estrutura Terciária de Proteína , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Fatores de Tempo , Fator de Transcrição AP-1/metabolismo , Transfecção , Fator de Crescimento Transformador beta1 , Ubiquitina/química , Regulação para Cima , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo , Proteína bcl-X/metabolismo
9.
Hepatology ; 38(6): 1540-51, 2003 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-14647065

RESUMO

Nuclear factor kappaB (NF-kappaB) is an antiapoptotic factor involved in development, regeneration, and neoplastic progression of the liver. Previously, we have shown that stabilization of inhibitor kappaB (IkappaB)-alpha protein following treatment of hepatocytes with transforming growth factor (TGF)-beta1 promoted NF-kappaB repression, which then permitted induction of AP-1/SMAD-mediated liver cell death. Because basal IkappaB-alpha protein turnover is regulated by protein kinase CK2, here we have elucidated the regulation of CK2 kinase activity and its role in control of NF-kappaB levels following treatment with TGF-beta1. We show that both messenger RNA (mRNA) and protein levels of the CK2alpha catalytic subunit are down-regulated following TGF-beta1 stimulation in murine hepatocyte cells. The ensuing inhibition of CK2 kinase activity promotes stabilization of IkappaB protein, which is followed by the shutoff of constitutive NF-kappaB activity and induction of apoptosis. Ectopic expression of CK2alpha inhibits TGF-beta1-induced apoptosis through sustained activation of NF-kappaB. Conversely, expression of a kinase-dead mutant of CK2alpha potentiates TGF-beta1 cell killing. Importantly, we show that hepatocellular carcinomas (HCCs) derived from TGF-beta1 transgenic mice and human HCC cell lines display enhanced CK2 IkappaB kinase activity that contributes in part to an elevated NF-kappaB activity in vivo. In conclusion, inhibition of CK2 expression levels by TGF-beta1 is crucial for the induction of apoptosis of hepatocytes. Circumvention of this process by up-regulation of CK2 activity in transformed cells may contribute to the promotion of TGF-beta1-induced liver carcinogenesis.


Assuntos
Apoptose , Hepatócitos/patologia , Proteínas I-kappa B/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Fator de Crescimento Transformador beta/farmacologia , Animais , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/etiologia , Caseína Quinase II , Células Cultivadas , Regulação para Baixo , Humanos , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/etiologia , Camundongos , Inibidor de NF-kappaB alfa , NF-kappa B/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/fisiologia , Fator de Crescimento Transformador beta1
10.
Mol Pharmacol ; 65(4): 1038-47, 2004 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15044634

RESUMO

Nuclear factor kappaB (NF-kappaB) has been implicated in inducible chemoresistance against anthracyclines. In an effort to improve the cytotoxicity of anthracyclines while reducing their cardiotoxic effects, we have developed a novel class of extranuclear-localizing 14-O-acylanthracyclines that bind to the phorbol ester/diacylglycerol-binding C1b domain of conventional and novel protein kinase C (PKC) isoforms, thereby promoting an apoptotic response. Because PKCs have been shown to be involved in NF-kappaB activation, in this report, we determined the mechanism of NF-kappaB activation by N-benzyladriamycin-14-valerate (AD 198) and N-benzyladriamycin-14-pivalate (AD 445), two novel 14-O-acylanthracylines. We show that the induction of NF-kappaB activity in response to drug treatment relies on the activation of PKC-delta and NF-kappaB-activating kinase (NAK), independent of ataxia telengectasia mutated and p53 activities. In turn, NAK activates the IKK complex through phosphorylation of the IKK-2 subunit. We find that neither NF-kappaB activation nor ectopic expression of Bcl-X(L) confers protection from AD 198-induced cell killing. Overall, our data indicate that activation of novel PKC isoforms by cytoplasmic-targeted 14-O-acylanthracyclines promotes an apoptotic response independent of DNA damage, which is unimpeded by inducible activation of NF-kappaB.


Assuntos
Antraciclinas/farmacologia , NF-kappa B/metabolismo , Proteína Quinase C/metabolismo , Animais , Proteínas Mutadas de Ataxia Telangiectasia , Proteínas de Ciclo Celular , Linhagem Celular , Citoplasma/efeitos dos fármacos , Citoplasma/enzimologia , Dano ao DNA , Proteínas de Ligação a DNA , Doxorrubicina/análogos & derivados , Doxorrubicina/farmacologia , Ativação Enzimática , Quinase I-kappa B , Camundongos , Proteína Quinase C-delta , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transfecção , Proteína Supressora de Tumor p53/metabolismo , Proteínas Supressoras de Tumor , Proteína bcl-X
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