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1.
Nature ; 501(7467): 421-5, 2013 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-23945590

RESUMO

Activated oncogenes and anticancer chemotherapy induce cellular senescence, a terminal growth arrest of viable cells characterized by S-phase entry-blocking histone 3 lysine 9 trimethylation (H3K9me3). Although therapy-induced senescence (TIS) improves long-term outcomes, potentially harmful properties of senescent tumour cells make their quantitative elimination a therapeutic priority. Here we use the Eµ-myc transgenic mouse lymphoma model in which TIS depends on the H3K9 histone methyltransferase Suv39h1 to show the mechanism and therapeutic exploitation of senescence-related metabolic reprogramming in vitro and in vivo. After senescence-inducing chemotherapy, TIS-competent lymphomas but not TIS-incompetent Suv39h1(-) lymphomas show increased glucose utilization and much higher ATP production. We demonstrate that this is linked to massive proteotoxic stress, which is a consequence of the senescence-associated secretory phenotype (SASP) described previously. SASP-producing TIS cells exhibited endoplasmic reticulum stress, an unfolded protein response (UPR), and increased ubiquitination, thereby targeting toxic proteins for autophagy in an acutely energy-consuming fashion. Accordingly, TIS lymphomas, unlike senescence models that lack a strong SASP response, were more sensitive to blocking glucose utilization or autophagy, which led to their selective elimination through caspase-12- and caspase-3-mediated endoplasmic-reticulum-related apoptosis. Consequently, pharmacological targeting of these metabolic demands on TIS induction in vivo prompted tumour regression and improved treatment outcomes further. These findings unveil the hypercatabolic nature of TIS that is therapeutically exploitable by synthetic lethal metabolic targeting.


Assuntos
Autofagia , Senescência Celular , Glucose/metabolismo , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/metabolismo , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Caspase 12/metabolismo , Caspase 3/metabolismo , Senescência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático , Feminino , Linfoma de Células B/genética , Linfoma de Células B/patologia , Masculino , Camundongos , Camundongos Transgênicos , Proteólise , Estresse Fisiológico , Taxa de Sobrevida
2.
J Clin Invest ; 124(12): 5263-74, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25384216

RESUMO

Multiple myeloma (MM) is a plasma cell neoplasm that results from clonal expansion of an Ig-secreting terminally differentiated B cell. Advanced MM is characterized by tissue damage that involves bone, kidney, and other organs and is typically associated with recurrent genetic abnormalities. IL-6 signaling via the IL-6 signal transducer GP130 has been implicated as an important driver of MM pathogenesis. Here, we demonstrated that ectopic expression of constitutively active GP130 (L-GP130) in a murine retroviral transduction-transplantation model induces rapid MM development of high penetrance. L-GP130-expressing mice recapitulated all of the characteristics of human disease, including monoclonal gammopathy, BM infiltration with lytic bone lesions, and protein deposition in the kidney. Moreover, the disease was easily transplantable and allowed different therapeutic options to be evaluated in vitro and in vivo. Using this model, we determined that GP130 signaling collaborated with MYC to induce MM and was responsible and sufficient for directing the plasma cell phenotype. Accordingly, we identified Myc aberrations in the L-GP130 MM model. Evaluation of human MM samples revealed recurrent activation of STAT3, a downstream target of GP130 signaling. Together, our results indicate that deregulated GP130 activity contributes to MM pathogenesis and that pathways downstream of GP130 activity have potential as therapeutic targets in MM.


Assuntos
Receptor gp130 de Citocina/metabolismo , Mieloma Múltiplo/metabolismo , Neoplasias Experimentais/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Animais , Linhagem Celular Tumoral , Receptor gp130 de Citocina/genética , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Plasmócitos/metabolismo , Plasmócitos/patologia , Proteínas Proto-Oncogênicas c-myc/genética , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/genética
3.
PLoS One ; 7(5): e37433, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22624029

RESUMO

The Cks1 component of the SCF(Skp2) complex is necessary for p27(Kip1) ubiquitylation and degradation. Cks1 expression is elevated in various B cell malignancies including Burkitt lymphoma and multiple myeloma. We have previously shown that loss of Cks1 results in elevated p27(Kip1) levels and delayed tumor development in a mouse model of Myc-induced B cell lymphoma. Surprisingly, loss of Skp2 in the same mouse model also resulted in elevated p27(Kip1) levels but exhibited no impact on tumor onset. This raises the possibility that Cks1 could have other oncogenic activities than suppressing p27(Kip1). To challenge this notion we have targeted overexpression of Cks1 to B cells using a conditional retroviral bone marrow transduction-transplantation system. Despite potent ectopic overexpression, Cks1 was unable to promote B cell hyperproliferation or B cell malignancies, indicating that Cks1 is not oncogenic when overexpressed in B cells. Since Skp2 overexpression can drive T-cell tumorigenesis or other cancers we also widened the quest for oncogenic activity of Cks1 by ubiquitously expressing Cks1 in hematopoetic progenitors. At variance with c-Myc overexpression, which caused acute myeloid leukemia, Cks1 overexpression did not induce myeloproliferation or leukemia. Therefore, despite being associated with a poor prognosis in various malignancies, sole Cks1 expression is insufficient to induce lymphoma or a myeloproliferative disease in vivo.


Assuntos
Quinases relacionadas a CDC2 e CDC28/metabolismo , Proliferação de Células , Regulação Neoplásica da Expressão Gênica/fisiologia , Neoplasias Hematológicas/metabolismo , Linfoma de Células B/metabolismo , Neoplasias/fisiopatologia , Animais , Medula Óssea/metabolismo , Citometria de Fluxo , Proteínas de Fluorescência Verde/metabolismo , Immunoblotting , Camundongos , Camundongos Transgênicos , Neoplasias/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Retroviridae
4.
Mol Cancer Res ; 8(3): 353-62, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20197382

RESUMO

The universal cyclin-dependent kinase inhibitor p27(Kip1) functions as a tumor suppressor, and reduced levels of p27(Kip1) connote poor prognosis in several human malignancies. p27(Kip1) levels are predominately regulated by ubiquitin-mediated turnover of the protein, which is marked for destruction by the E3 ubiquitin ligase SCF(Skp2) complex following its phosphorylation by the cyclin E-cyclin-dependent kinase 2 complex. Binding of phospho-p27(Kip1) is directed by the Skp2 F-box protein, and this is greatly augmented by its allosteric regulator Cks1. We have established that programmed expression of c-Myc in the B cells of Emu-Myc transgenic mice triggers p27(Kip1) destruction by inducing Cks1, that this response controls Myc-driven proliferation, and that loss of Cks1 markedly delays Myc-induced lymphomagenesis and cancels the dissemination of these tumors. Here, we report that elevated levels of Skp2 are a characteristic of Emu-Myc lymphomas and of human Burkitt lymphoma that bear MYC/Immunoglobulin chromosomal translocations. As expected, Myc-mediated suppression of p27(Kip1) was abolished in Skp2-null Emu-Myc B cells. However, the effect of Skp2 loss on Myc-driven proliferation and lymphomagenesis was surprisingly modest compared with the effects of Cks1 loss. Collectively, these findings suggest that Cks1 targets, in addition to p27(Kip1), are critical for Myc-driven proliferation and tumorigenesis.


Assuntos
Proteínas de Transporte/metabolismo , Transformação Celular Neoplásica/metabolismo , Quinases Ciclina-Dependentes/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Linfoma de Células B/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Quinases Associadas a Fase S/metabolismo , Animais , Quinases relacionadas a CDC2 e CDC28 , Proteínas de Transporte/genética , Proliferação de Células , Transformação Celular Neoplásica/genética , Células Cultivadas , Inibidor de Quinase Dependente de Ciclina p27 , Quinases Ciclina-Dependentes/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Linfoma de Células B/genética , Linfoma de Células B/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Quinases Associadas a Fase S/genética , Células Tumorais Cultivadas , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Regulação para Cima/fisiologia
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