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1.
Oncoimmunology ; 7(8): e1466769, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30221069

RESUMO

The use of inhibitory checkpoint blockade in the management of glioblastoma has been studied in both preclinical and clinical settings. TIGIT is a novel checkpoint inhibitor recently discovered to play a role in cancer immunity. In this study, we sought to determine the effect of anti-PD-1 and anti-TIGIT combination therapy on survival in a murine glioblastoma (GBM) model, and to elucidate the underlying immune mechanisms. Using mice with intracranial GL261-luc+ tumors, we found that TIGIT expression was upregulated on CD8+ and regulatory T cells (Tregs) in the brain compared to draining cervical lymph nodes (CLN) and spleen. We then demonstrated that treatment using anti-PD-1 and anti-TIGIT dual therapy significantly improved survival compared to control and monotherapy groups. The therapeutic effect was correlated with both increased effector T cell function and downregulation of suppressive Tregs and tumor-infiltrating dendritic cells (TIDCs). Clinically, TIGIT expression on tumor-infiltrating lymphocytes was shown to be elevated in patient GBM samples, suggesting that the TIGIT pathway may be a valuable therapeutic target. Expression of the TIGIT ligand, PVR, further portended a poor survival outcome in patients with low-grade glioma. We conclude that anti-TIGIT is an effective treatment strategy against murine GBM when used in combination with anti-PD-1, improving overall survival via modifications of both the T cell and myeloid compartments. Given evidence of PVR expression on human GBM cells, TIGIT presents as a promising immune therapeutic target in the management of these patients.

2.
SLAS Discov ; 23(7): 742-750, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29873570

RESUMO

Enhancing antitumor activities of the human immune system is a clinically proven approach with the advent of monoclonal antibodies recognizing programmed cell death protein-1 (PD1) receptors on immune cell surfaces. Historically, using flow cytometry as a means to assess next-generation agent activities was underused, largely due to limits on cell number and assay sensitivity. Here, we leveraged an IntelliCyt high-throughput flow cytometry platform to monitor human dendritic cell maturation and lymphocyte proliferation in mixed lymphocyte reactions. Specifically, we established flow cytometry-based immunophenotyping and screening methodologies capable of measuring T-cell activation as a result of cell-associated antigens presented on dendritic cell surfaces, as indicated by cell proliferation, cytokine secretion, and surface marker expression. Together, the overall novelty of this 384-well platform is its capability to measure multiple functional readouts in one well and consistently evaluate large numbers of compounds in a single study, as well as its ability to show increased assay sensitivity requiring considerably fewer primary cells and less reagents compared to more traditional 96-well flow cytometry methods.


Assuntos
Células Dendríticas/metabolismo , Citometria de Fluxo , Ensaios de Triagem em Larga Escala , Ativação Linfocitária , Teste de Cultura Mista de Linfócitos , Linfócitos T/metabolismo , Citocinas/metabolismo , Células Dendríticas/imunologia , Citometria de Fluxo/métodos , Humanos , Ativação Linfocitária/imunologia , Linfócitos T/imunologia
3.
Immunol Cell Biol ; 95(4): 340-346, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27974746

RESUMO

The use of antibody therapy for cancer has steadily increased in recent years and has become standard treatment for numerous tumor types. It is now appreciated that the clinical activity of these antibodies relies upon their specific interactions with Fc receptors in addition to the well-studied target-binding region. The interactions mediated by antibody Fc domains can strongly affect the functional outcome of antibody therapy. The Fc portion of an antibody defines its interaction with numerous immune cells and has become an intense area of research as selecting the optimal Fc can greatly enhance the activity as well as mechanism of action of therapeutic antibodies. Recent advances in antibody engineering have enabled the development of antibodies that have altered Fc receptor interactions to take advantage of these findings. Engineering the Fc can fulfill diverse functions such as enhancing effector function for killing of tumor cells or depletion of unwanted immune subsets, enhancing agonist receptor signaling on particular immune cells or eliminating interaction with Fc receptors to avoid cellular depletion or toxicity in normal tissues. This review highlights important data and studies examining the role of Fc-Fc receptor interactions in therapeutic antibodies with a considerations for the future of engineered antibody therapy.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Imunoterapia/métodos , Neoplasias/terapia , Receptores Fc/metabolismo , Receptores de IgG/metabolismo , Animais , Humanos , Neoplasias/imunologia , Ligação Proteica , Engenharia de Proteínas , Transdução de Sinais
4.
Cancer Cell ; 29(6): 820-831, 2016 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-27265505

RESUMO

While engagement of the inhibitory Fcγ-receptor (FcγR) IIB is an absolute requirement for in vivo antitumor activity of agonistic mouse anti-CD40 monoclonal antibodies (mAbs), a similar requirement for human mAbs has been disputed. By using a mouse model humanized for its FcγRs and CD40, we revealed that FcγRIIB engagement is essential for the activity of human CD40 mAbs, while engagement of the activating FcγRIIA inhibits this activity. By engineering Fc variants with selective enhanced binding to FcγRIIB, but not to FcγRIIA, significantly improved antitumor immunity was observed. These findings highlight the necessity of optimizing the Fc domain for this class of therapeutic antibodies by using appropriate preclinical models that accurately reflect the unique affinities and cellular expression of human FcγR.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Antígenos CD40/agonistas , Neoplasias/tratamento farmacológico , Receptores de IgG/imunologia , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais Humanizados/imunologia , Linhagem Celular Tumoral , Humanos , Imunoterapia , Camundongos , Neoplasias/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Exp Cell Res ; 338(2): 251-60, 2015 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-26302264

RESUMO

Cellular levels of inhibitor of apoptosis (IAP) proteins are elevated in multiple human cancers and their activities often play a part in promoting cancer cell survival by blocking apoptotic pathways, controlling signal transduction pathways and contributing to resistance. These proteins function through interactions of their BIR (baculoviral IAP repeat) protein domains with pathway components and these interactions are endogenously antagonized by Smac/Diablo (second mitochondrial activator of caspases/direct IAP binding protein with low isoelectric point). This report describes development of synthetic smac mimetics (SM) and compares their binding, antiproliferative and anti-tumor activities. All dimeric antagonists inhibit in vitro smac tetrapeptide binding to recombinant IAP proteins, rescue IAP-bound caspase-3 activity and show anti-proliferative activity against human A875 melanoma cells. One heterodimeric SM, SM3, binds tightly to IAP proteins in vitro and slowly dissociates (greater than two hours) from these protein complexes compared to the other antagonists. In addition, in vitro SM anti-proliferation potency is influenced by ABCB1 transporter (ATP-binding cassette, sub-family B; MDR1, P-gp) activities and one antagonist, SM5, does not appear to be an ABCB1 efflux pump substrate. All dimeric smac mimetics inhibit the growth of human melanoma A875 tumors implanted in athymic mice at well-tolerated doses. One antagonist, SM4, shows broad spectrum in vivo anti-tumor activity and modulates known pharmacodynamic markers of IAP antagonism. These data taken together demonstrate the range of diverse dimeric IAP antagonist activities and supports their potential as anticancer agents.


Assuntos
Antineoplásicos/farmacologia , Transporte Biológico/efeitos dos fármacos , Caspase 3/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Proteínas Mitocondriais/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose , Biomimética/métodos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Células HCT116 , Humanos , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , Ligação Proteica/efeitos dos fármacos , Estrutura Terciária de Proteína/efeitos dos fármacos
6.
Cancer Biol Ther ; 7(9): 1441-9, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18708753

RESUMO

Elevated activity of the eIF4F complex, which controls initiation of cap-dependent mRNA translation, has been linked to cancer progression. eIF4E recruitment to eIF4F is the rate limiting step of complex assembly and is regulated by eIF4E-Binding Proteins (4E-BPs). When stimulated, the mammalian Target of Rapamycin complex 1 (mTORC1) phosphorylates 4E-BP1, which then releases eIF4E. Hypoxia inhibits mTORC1 activity and therefore cap-dependent protein synthesis. To establish a novel genetic test of the role of eIF4F activity in regulating cell division and viability within hypoxic tumor microenvironments, we generated shRNA mediated 4E-BP1 knock-down in Rh30 rhabdomyosarcoma cells. 4E-BP1 knock-down relieved hypoxia-mediated inhibition of cycle progression in vitro and was correlated with increased expression of cyclin D1 and c-Myc. Xenograft tumors derived from these cells also displayed enhanced expression of cyclin D1 and c-Myc along with antiapoptotic genes encoding Bcl-x(L), and XIAP, and failed to develop the extensive necrotic zones and edema observed in control tumors. Surprisingly, 4E-BP1 knock-down also leads to a dramatic increase in aberrant mitoses in vivo and enhanced expression of Mad2 and securin. Thus, reduced expression of the negative regulator of eIF4E has significant effects on tumor development, and is associated with enhanced cell proliferation and survival.


Assuntos
Ciclo Celular , Proliferação de Células , Fator de Iniciação 4E em Eucariotos/metabolismo , Hipóxia/metabolismo , Neoplasias/metabolismo , Animais , Sobrevivência Celular , Estruturas Celulares/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Hipóxia/genética , Imuno-Histoquímica , Camundongos , Camundongos Nus , Neoplasias/genética , RNA Interferente Pequeno/metabolismo , Rabdomiossarcoma/genética , Rabdomiossarcoma/metabolismo , Rabdomiossarcoma/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
7.
Annu Rev Physiol ; 70: 51-71, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-17850210

RESUMO

Low oxygen (O2) levels are a naturally occurring feature of embryonic development, adult physiology, and diseases such as those of the cardiovascular system. Although many responses to O2 deprivation are mediated by hypoxia-inducible factors (HIFs), researchers are finding a growing number of HIF-independent pathways that promote O2 conformance and hypoxia tolerance. Here, we describe HIF-independent responses and how they impact cardiovascular tissue homeostasis.


Assuntos
Sistema Cardiovascular/metabolismo , Hipóxia/metabolismo , Oxigênio/metabolismo , Transdução de Sinais/fisiologia , Animais , Homeostase/fisiologia , Humanos , Isquemia/metabolismo
8.
J Clin Invest ; 117(9): 2385-8, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17786234

RESUMO

Increased cap-dependent mRNA translation rates are frequently observed in human cancers. Mechanistically, many human tumors often overexpress the cap binding protein eukaryotic translation initiation factor 4E (eIF4E), leading to enhanced translation of numerous tumor-promoting genes. In this issue of the JCI, Graff and colleagues describe potent antitumor effects using second-generation antisense oligonucleotides for eIF4E (see the related article beginning on page 2638). If their results are recapitulated in a clinical setting, this strategy will provide a promising antitumor therapy with broad-reaching applications.


Assuntos
Neoplasias/genética , Biossíntese de Proteínas/genética , Animais , Regulação para Baixo , Fator de Iniciação 4E em Eucariotos/genética , Fator de Iniciação 4E em Eucariotos/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/terapia
9.
Cancer Metastasis Rev ; 26(2): 261-71, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17647111

RESUMO

Recent studies have described a small population of self-renewing and multipotent cells within tumors termed "cancer stem cells." These cells share many traits with somatic and embryonic stem cells and are thought to be responsible for driving tumor progression in a growing list of neoplastic diseases. Cells within solid tumors encounter hypoxia due to poor vascular function. Both long-standing and emerging data describe hypoxic effects on somatic and embryonic stem cells, and it is likely that hypoxia also has profound effects on cancer stem cells. These effects include the activation of pathways that induce the dedifferentiation of cancer cells, the maintenance of stem cell identity, and increased metastatic potential. Hypoxia may contribute to tumor progression by specifically impacting these pathways in cancer stem cells.


Assuntos
Hipóxia Celular/fisiologia , Metástase Neoplásica/fisiopatologia , Células-Tronco/fisiologia , Translocador Nuclear Receptor Aril Hidrocarboneto/genética , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Metástase Neoplásica/patologia , Células-Tronco/patologia
10.
Biochim Biophys Acta ; 1755(1): 25-36, 2005 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-15907590

RESUMO

CD95 (APO-1/Fas) is an important inducer of the extrinsic apoptosis signaling pathway and therapy induced apoptosis of many tumor cells has been linked to the activity of CD95. Changes in the expression of CD95 and/or its ligand CD95L are frequently found in human cancer. The downregulation or mutation of CD95 has been proposed as a mechanism by which cancer cells avoid destruction by the immune system through reduced apoptosis sensitivity. CD95 has therefore been viewed as a tumor suppressor. Furthermore, increased CD95L concentration in tumor patients has been linked to tumor cells killing infiltrating lymphocytes in a process called "the tumor counter-attack". Recent data have illuminated unknown activities of CD95 in tumor cells with downregulated or mutated CD95 in the presence of increased CD95L. Under these conditions the stimulation of CD95 signals nonapoptotic pathways, activating NF-kappaB and MAP kinases for example, which may result in the induction of tumorigenic or prosurvival genes. A new model of CD95 functions is proposed in which CD95 is converted from a tumor suppressor to a tumor promotor by a single point mutation in one of the CD95 alleles, a situation frequently found in advanced human cancer, resulting in apoptosis resistance and activation of tumorigenic pathways.


Assuntos
Neoplasias/metabolismo , Receptor fas/fisiologia , Animais , Apoptose , Progressão da Doença , Regulação para Baixo , Proteína Ligante Fas , Humanos , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos MRL lpr , Modelos Biológicos , Mutação , Neoplasias/terapia , Transdução de Sinais
11.
Cell Cycle ; 3(10): 1235-9, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15467462

RESUMO

Most members of the death receptor family including CD95 (APO-1/Fas) have been shown to induce both apoptosis as well as non-apoptotic pathways depending on the tissue and the circumstances. One of the non-apoptotic pathways emanating from CD95, activation of NF-kappaB, has recently been demonstrated to regulate invasiveness of apoptosis resistant tumor cells. In contrast, activation of NF-kappaB in apoptosing cells is believed to be suppressed due to cleavage of various NF-kappaB pathway components by active caspases that execute apoptosis. We now present data demonstrating that in certain highly CD95 apoptosis sensitive cells NF-kappaB is robustly activated. In fact overexpression of apoptosis inhibitors such as Bcl-2 or c-FLIPL in these cells results in decreased activation of NF-kappaB through CD95. We propose a model in which NF-kappaB is generally activated in certain cells but may have different functions depending on whether cells are programmed to die or to survive.


Assuntos
NF-kappa B/metabolismo , Neoplasias/metabolismo , Transdução de Sinais , Receptor fas/metabolismo , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD , Regulação para Baixo/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Modelos Biológicos , Neoplasias/patologia
12.
EMBO Rep ; 5(11): 1084-9, 2004 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-15514680

RESUMO

Mutations in the death domain of the death receptor CD95 (APO-1/Fas) cause lymphoproliferation and autoimmune disease in both lpr(cg) mice and in patients with autoimmune lymphoproliferative syndrome (ALPS) type Ia. By testing lymphocytes from ALPS type Ia patients, comparing heterozygous with homozygous lpr(cg) mice and coexpressing wild-type and mutant CD95 receptors, we demonstrate that induction of apoptosis requires two wild-type alleles of CD95. By contrast, nuclear factor-kappaB (NF-kappaB) can be fully activated in cells expressing both a mutant and a wild-type CD95 allele, suggesting different thresholds to activate the two signalling pathways. This was confirmed by testing lymphocytes from heterozygous lpr mice, which showed reduced sensitivity to CD95-mediated apoptosis but normal activation of NF-kappaB when compared with wild-type mice. Mutations in CD95 may eliminate the tumour-suppressive function of CD95, at the same time allowing induction of survival or proliferative pathways, which could contribute to the increased risk for lymphoma seen in ALPS type Ia patients.


Assuntos
Apoptose , NF-kappa B/metabolismo , Transdução de Sinais , Receptor fas/biossíntese , Alelos , Animais , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Cloranfenicol O-Acetiltransferase/metabolismo , Ensaio de Imunoadsorção Enzimática , Éxons , Heterozigoto , Homozigoto , Humanos , Ligantes , Linfócitos/metabolismo , Camundongos , Modelos Biológicos , Mutação , Plasmídeos/metabolismo , Baço/citologia , Baço/metabolismo , Fatores de Tempo
13.
J Biol Chem ; 279(45): 46742-7, 2004 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-15345718

RESUMO

The death receptor CD95 (APO-1/Fas) induces apoptosis in many tissues. However, in apoptosis-resistant tumor cells, stimulation of CD95 induces up-regulation of a defined number of mostly anti-apoptotic genes, resulting in increased motility and invasiveness of tumor cells. The majority of these genes are known NF-kappaB target genes. We have identified one of the CD95-regulated genes as the serine/threonine kinase (SNF1/AMP kinase-related kinase (SNARK)), which is induced in response to various forms of metabolic stress. We demonstrate that up-regulation of SNARK in response to CD95 ligand and tumor necrosis factor alpha depends on activation of NF-kappaB. Overexpression of SNARK rendered tumor cells more resistant, whereas a kinase-inactive mutant of SNARK sensitized cells to CD95-mediated apoptosis. Furthermore, small interfering RNA-mediated knockdown of SNARK increased the sensitivity of tumor cells to CD95 ligand- and TRAIL-induced apoptosis. Importantly, cells with reduced expression of SNARK also showed reduced motility and invasiveness in response to CD95 engagement. SNARK therefore represents an NF-kappaB-regulated anti-apoptotic gene that contributes to the tumor-promoting activity of CD95 in apoptosis-resistant tumor cells.


Assuntos
Apoptose , NF-kappa B/metabolismo , Proteínas Serina-Treonina Quinases/fisiologia , Receptor fas/biossíntese , Western Blotting , Morte Celular , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular , Sobrevivência Celular , Relação Dose-Resposta a Droga , Glutationa Transferase/metabolismo , Células HeLa , Humanos , Mutagênese Sítio-Dirigida , Invasividade Neoplásica , Fosforilação , Plasmídeos/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , RNA Interferente Pequeno/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima
14.
EMBO J ; 23(15): 3175-85, 2004 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-15272306

RESUMO

The apoptosis-inducing death receptor CD95 (APO-1/Fas) controls the homeostasis of many tissues. Despite its apoptotic potential, most human tumors are refractory to the cytotoxic effects of CD95 ligand. We now show that CD95 stimulation of multiple apoptosis-resistant tumor cells by CD95 ligand induces increased motility and invasiveness, a response much less efficiently triggered by TNFalpha or TRAIL. Three signaling pathways resulting in activation of NF-kappaB, Erk1/2 and caspase-8 were found to be important to this novel activity of CD95. Gene chip analyses of a CD95-stimulated tumor cell line identified a number of potential survival genes and genes that are known to regulate increased motility and invasiveness of tumor cells to be induced. Among these genes, urokinase plasminogen activator was found to be required for the CD95 ligand-induced motility and invasiveness. Our data suggest that CD95L, which is found elevated in many human cancer patients, has tumorigenic activities on human cancer cells. This could become highly relevant during chemotherapy, which can cause upregulation of CD95 ligand by both tumor and nontumor cells.


Assuntos
Apoptose , Movimento Celular , Glicoproteínas de Membrana/metabolismo , Invasividade Neoplásica/patologia , Neoplasias/metabolismo , Neoplasias/patologia , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose , Caspase 8 , Caspases/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células , Transformação Celular Neoplásica/genética , Células Cultivadas , Proteína Ligante Fas , Humanos , Sistema de Sinalização das MAP Quinases , Glicoproteínas de Membrana/farmacologia , NF-kappa B/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF , Fatores de Transcrição/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Regulação para Cima , Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Receptor fas/metabolismo
15.
Oncogene ; 22(53): 8634-44, 2003 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-14634625

RESUMO

Apoptosis signaling is regulated and executed by specialized proteins that often carry protein/protein interaction domains. One of these domains is the death effector domain (DED) that is predominantly found in components of the death-inducing signaling complex, which forms at the members of the death receptor family following their ligation. Both proapoptotic- and antiapoptotic-DED-containing proteins have been identified, which makes these proteins exquisitely suited to the regulation of apoptosis. Aside from their pivotal role in the control of the apoptotic program, DED-containing proteins have recently been demonstrated to exert their influence on other cellular processes as well, including cell proliferation. These data highlight the multiple roles for the members of this family, suggesting that they are suited to control both life and death decisions of cells. Additionally, because they can act proapoptotically, antiapoptotically, or in the regulation of the cell cycle, this family of proteins may be excellent candidates for cancer therapy targets. Oncogene (2003) 22, 8634-8644. doi:10.1038/sj.onc.1207103


Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Apoptose , Proteínas de Ligação a DNA , Peptídeos e Proteínas de Sinalização Intracelular , Sequência de Aminoácidos , Animais , Proteínas Reguladoras de Apoptose , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD , Proteínas de Transporte/fisiologia , Caspase 10 , Caspase 8 , Caspase 9 , Caspases/fisiologia , Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte , Proteína de Domínio de Morte Associada a Fas , Humanos , Dados de Sequência Molecular , Neoplasias/terapia , Proteínas Nucleares/fisiologia , Fosfoproteínas/fisiologia , Proteínas/fisiologia
16.
Semin Immunol ; 15(3): 185-93, 2003 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-14563117

RESUMO

CD95 (APO-1/Fas) has become the prototype of a death domain containing receptor and is the best studied member of the death receptors that activate the extrinsic apoptosis pathway. This pathway is initiated by recruitment and activation of caspase-8, an initiator caspase, in the death-inducing signaling complex (DISC) followed by direct cleavage of downstream effector caspases. In contrast, the intrinsic apoptosis pathway starts from within the cell either by direct activation of caspases or through intracellular changes such as DNA damage resulting in the release of a number of pro-apoptotic factors from the intermembrane space of mitochondria. The release of these factors results in the activation of another initiator caspase, caspase-9, and ultimately in the activation of effector caspases in a protein complex called the apoptosome. In recent years, it has become apparent that there is cross talk between the extrinsic and intrinsic pathway. In the death receptor pathway of apoptosis induction, the best characterized connection between the two pathways is the Bcl-2 family member Bid which translocates to mitochondria after cleavage by caspase-8 causing pro-apoptotic changes. Cells that die through CD95 without help from mitochondria are called Type I cells, whereas cells in which CD95-mediated death relies mostly on the intrinsic pathway are called Type II. This review focuses on recent developments in the delineation of the biochemistry and the physiological function of the two CD95 pathways.


Assuntos
Mitocôndrias/metabolismo , Transdução de Sinais , Receptor fas/metabolismo , Animais , Proteína Ligante Fas , Humanos , Glicoproteínas de Membrana/química , Glicoproteínas de Membrana/metabolismo , Modelos Imunológicos , Receptor fas/imunologia
17.
Proc Natl Acad Sci U S A ; 100(20): 11445-50, 2003 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-14504390

RESUMO

CD95 type I and II cells differ in their dependence on mitochondria to execute apoptosis, because antiapoptotic members of the Bcl-2 family render only type II cells resistant to death receptor-induced apoptosis. They can also be distinguished by a more efficient formation of the death-inducing signaling complex in type I cells. We have identified a soluble form of CD95 ligand (S2) that is cytotoxic to type II cells but does not kill type I cells. By testing 58 tumor cell lines of the National Cancer Institute's anticancer drug-screening panel for apoptosis sensitivity to S2 and performing death-inducing signaling complex analyses, we determined that half of the CD95-sensitive cells are type I and half are type II. Most of the type I cell lines fall into a distinct class of tumor cells expressing mesenchymal-like genes, whereas the type II cell lines preferentially express epithelium-like markers. This suggests that type I and II tumor cells represent different stages of carcinogenesis that resemble the epithelial-mesenchymal transition. We then screened the National Cancer Institute database of >42,000 compounds for reagents with patterns of growth inhibition that correlated with either type I or type II cell lines and found that actin-binding compounds selectively inhibited growth of type I cells, whereas tubulin-interacting compounds inhibited growth of type II cells. Our analysis reveals fundamental differences in programs of gene expression between type I and type II cells and could impact the way actin- and microtubule-disrupting antitumor agents are used in tumor therapy.


Assuntos
Antineoplásicos/farmacologia , Neoplasias/patologia , Receptor fas/imunologia , Apoptose , Linhagem Celular , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias/imunologia
18.
Cell ; 114(2): 148-50, 2003 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-12887914

RESUMO

The tumor necrosis factor receptor 1 (TNFR1), a prototypic member of the death receptor family signals both cell survival and apoptosis. In this issue of Cell, report that apoptotic TNFR1 signaling proceeds via the sequential formation of two distinct complexes. Since the first complex can activate survival signals and influence the activity of the second complex, this mechanism provides a checkpoint to control the execution of apoptosis.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Apoptose/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas/metabolismo , Proteínas de Ligação a RNA , Receptores do Fator de Necrose Tumoral/metabolismo , Transdução de Sinais , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD , Proteínas de Transporte/metabolismo , Caspase 8 , Caspase 9 , Caspases/metabolismo , Sobrevivência Celular , Proteína de Domínio de Morte Associada a Fas , Humanos , Modelos Biológicos , NF-kappa B/efeitos dos fármacos , NF-kappa B/genética , NF-kappa B/metabolismo , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Processamento de Proteína Pós-Traducional , Proteínas/genética , Proteínas/imunologia , Receptores do Fator de Necrose Tumoral/genética , Receptores do Fator de Necrose Tumoral/imunologia , Fator 1 Associado a Receptor de TNF , Ativação Transcricional , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Receptor fas/metabolismo
19.
Curr Opin Cell Biol ; 14(6): 721-6, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12473345

RESUMO

Caspases are well known for their role in the execution of the apoptotic program by cleaving specific target proteins, leading to the dismantling of the cell, as well as for mediating cytokine maturation. Recent work has highlighted novel non-apoptotic activities of apoptotic caspases. These reports indicate that caspases are much more versatile enzymes than we originally expected. In addition to regulating cell survival and cytokine maturation, caspases may be involved in regulating cell differentiation, cell proliferation, spreading and receptor internalization.


Assuntos
Caspases/fisiologia , Animais , Apoptose , Ciclo Celular , Divisão Celular , Movimento Celular , Sobrevivência Celular , Modelos Biológicos , Receptores de Superfície Celular/metabolismo
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