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1.
Blood ; 122(14): 2402-11, 2013 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-23966420

RESUMO

Caloric restriction (CR) is proposed to decrease tumorigenesis through a variety of mechanisms including effects on glycolysis. However, the understanding of how CR affects the response to cancer therapy is still rudimentary. Here, using the Eµ-Myc transgenic mouse model of B-cell lymphoma, we report that by reducing protein translation, CR can reduce expression of the prosurvival Bcl-2 family member Mcl-1 and sensitize lymphomas to ABT-737-induced death in vivo. By using Eµ-Myc lymphoma cells lacking p53, we showed that CR mimetics such as 2-deoxyglucose led to a decrease in Mcl-1 expression and sensitized lymphoma cells to ABT-737-induced death independently of p53. In keeping with this, Eµ-Myc lymphoma cells lacking the BH3-only proapoptotic members Noxa, Puma, or Bim were also sensitized by CR mimetics to ABT-737-induced death. Remarkably, neither the loss of both Puma and Noxa, the loss of both Puma and Bim, nor the loss of all three BH3-only proteins prevented sensitization to ABT-737 induced by CR mimetics. Thus, CR can influence Mcl-1 expression and sensitize cells to BH3 mimetic-induced apoptosis, independently of the main BH3-only proteins and of p53. Exploiting this may improve the efficiency of, or prevent resistance to, cancer therapy.


Assuntos
Restrição Calórica , Resistencia a Medicamentos Antineoplásicos/fisiologia , Linfoma de Células B/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/metabolismo , Compostos de Bifenilo/farmacologia , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Proteína de Sequência 1 de Leucemia de Células Mieloides , Nitrofenóis/farmacologia , Piperazinas/farmacologia , Sulfonamidas/farmacologia
2.
Proc Natl Acad Sci U S A ; 109(49): 20071-6, 2012 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-23169636

RESUMO

Most DNA-damaging agents are weak inducers of an anticancer immune response. Increased glycolysis is one of the best-described hallmarks of tumor cells; therefore, we investigated the impact of glycolysis inhibition, using 2-deoxyglucose (2DG), in combination with cytotoxic agents on the induction of immunogenic cell death. We demonstrated that 2DG synergized with etoposide-induced cytotoxicity and significantly increased the life span of immunocompetent mice but not immunodeficient mice. We then established that only cotreated cells induced an efficient tumor-specific T-cell activation ex vivo and that tumor antigen-specific T cells could only be isolated from cotreated animals. In addition, only when mice were immunized with cotreated dead tumor cells could they be protected (vaccinated) from a subsequent challenge using the same tumor in viable form. Finally, we demonstrated that this effect was at least partially mediated through ERp57/calreticulin exposure on the plasma membrane. These data identify that the targeting of glycolysis can convert conventional tolerogenic cancer cell death stimuli into immunogenic ones, thus creating new strategies for immunogenic chemotherapy.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Morte Celular/imunologia , Desoxiglucose/farmacologia , Etoposídeo/farmacologia , Glicólise/efeitos dos fármacos , Linfoma de Células B/tratamento farmacológico , Animais , Western Blotting , Calreticulina/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Quimioterapia Combinada , Estimativa de Kaplan-Meier , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Interferência de RNA , Linfócitos T/efeitos dos fármacos
3.
Blood ; 113(2): 347-57, 2009 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-18849489

RESUMO

By presenting antigenic peptides on the cell surface, human leukocyte antigen (HLA) class I molecules are critical for immune defense. Their surface density determines, to a large extent, the level of CD8(+) T cell-dependent immune reactions; their loss is a major mechanism of immune escape. Therefore, powerful processes should regulate their surface expression. Here we document the mechanisms used by CD99 to mediate HLA class I modulation. Up-regulation of HLA class I by IFN-gamma requires CD99. In the trans Golgi network (TGN), and up to the cell surface, CD99 and HLA class I are physically associated via their transmembrane domain. CD99 also binds p230/golgin-245, a coiled-coil protein that recycles between the cytosol and buds/vesicles of the TGN and which plays a fundamental role in trafficking transport vesicles. p230/golgin-245 is anchored within TGN membranes via its Golgin-97, RanBP1, IMh1p, P230 (GRIP) domain and the overexpression of which leads to surface and intracellular down-modulation of HLA class I molecules.


Assuntos
Antígenos CD/imunologia , Autoantígenos/imunologia , Linfócitos T CD8-Positivos/imunologia , Moléculas de Adesão Celular/imunologia , Complexo de Golgi/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Proteínas de Membrana/imunologia , Regulação para Cima/imunologia , Antígeno 12E7 , Antígenos CD/metabolismo , Antivirais/imunologia , Antivirais/farmacologia , Autoantígenos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Moléculas de Adesão Celular/metabolismo , Citosol/imunologia , Citosol/metabolismo , Complexo de Golgi/metabolismo , Antígenos HLA/biossíntese , Antígenos HLA/imunologia , Antígenos de Histocompatibilidade Classe I/biossíntese , Humanos , Imunidade Celular/fisiologia , Interferon gama/imunologia , Interferon gama/farmacologia , Células Jurkat , Proteínas de Membrana/metabolismo , Estrutura Terciária de Proteína/fisiologia , Transporte Proteico/efeitos dos fármacos , Transporte Proteico/imunologia , Vesículas Transportadoras/imunologia , Vesículas Transportadoras/metabolismo , Regulação para Cima/efeitos dos fármacos
4.
Cell Death Dis ; 11(12): 1041, 2020 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-33288741

RESUMO

Escape from cell death is a key event in cancer establishment/progression. While apoptosis is often considered as the main cell death pathway, upon caspase inhibition, cell death is rather delayed than blocked leading to caspase-independent cell death (CICD). Although described for years, CICD's underlying mechanism remains to be identified. Here, we performed a genome-wide siRNA lethality screening and identified the RING-Type E3 Ubiquitin Transferase (UBR2) as a specific regulator of CICD. Strikingly, UBR2 downregulation sensitized cells towards CICD while its overexpression was protective. We established that UBR2-dependent protection from CICD was mediated by the MAPK/Erk pathway. We then observed that UBR2 is overexpressed in several cancers, especially in breast cancers and contributes to CICD resistance. Therefore, our work defines UBR2 as a novel regulator of CICD, found overexpressed in cancer cells, suggesting that its targeting may represent an innovative way to kill tumor cells.


Assuntos
Caspases/deficiência , Sistema de Sinalização das MAP Quinases , Ubiquitina-Proteína Ligases/metabolismo , Apoptose , Autofagia , Caspases/metabolismo , Morte Celular , Linhagem Celular Tumoral , Citoproteção , Ferroptose , Técnicas de Silenciamento de Genes , Genoma Humano , Humanos , Modelos Biológicos , Necroptose
5.
Trends Mol Med ; 20(8): 419-27, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24916302

RESUMO

Caloric restriction (CR) is currently the most robust environmental intervention known to increase healthy life and prolong lifespan in several models, from yeast to mice. Although the protective effect of CR on the incidence of cancer is well established, its impact on tumor cell responses to chemotherapeutic treatment is currently being investigated. Interestingly, the molecular mechanisms required to extend lifespan upon reduced food intake are being evaluated, and these mechanisms may offer new opportunities for therapeutic intervention. In addition, new findings suggest a beneficial effect of CR in enhancing the efficiency of tumor cell killing by chemotherapeutic drugs and inducing an anticancer immune response.


Assuntos
Restrição Calórica , Neoplasias/dietoterapia , Neoplasias/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Restrição Calórica/métodos , Terapia Combinada/métodos , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Serina-Treonina Quinases TOR/metabolismo
6.
Cancer Res ; 70(9): 3730-8, 2010 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-20388798

RESUMO

Ewing's sarcoma (EWS) is an aggressive tumor of children and young adults that requires intensive treatment. The search for new prognostic factors is very important to choose the most appropriate therapy and to better understand the biology of the disease for the development of new therapeutic tools. We found that Xg, a thus far poorly described molecule and member of the CD99 family, is expressed in EWS cell lines and EWS primary tumors. Immunohistochemical analysis confirmed the expression of Xg in 24% of patients. We found that Xg expression in EWS defines a subgroup of patients with worse prognosis compared with those with Xg-negative localized tumors, indicating a clinical relevance of Xg expression in EWS. Forced expression of Xg in an EWS cell line upregulated cell migration and invasion in vitro. Furthermore, knockdown of Xg expression with specific short hairpin RNA significantly reduced migration and invasion of EWS cells. Consistent with these data, in vivo xenotransplant studies in nude mice revealed that Xg expression increased the incidence and the number of metastases of EWS cells. Thus, Xg expression is associated with lower overall survival in EWS patients with localized tumors and is implicated in metastasis.


Assuntos
Antígenos de Grupos Sanguíneos/biossíntese , Moléculas de Adesão Celular/biossíntese , Sarcoma de Ewing/metabolismo , Adolescente , Animais , Neoplasias Ósseas/imunologia , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Criança , Feminino , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Masculino , Camundongos , Camundongos Nus , Invasividade Neoplásica , Osteossarcoma/imunologia , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Prognóstico , Sarcoma de Ewing/imunologia , Sarcoma de Ewing/patologia
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