RESUMEN
Polycomb group (PcG) proteins are chromatin modifiers that are necessary for the maintenance and renewal of embryonic and adult stem cells. However, overexpression of the PcG protein, Bmi-1, causes lymphoma in transgenic mice. We show that Bmi-1 is up-regulated in Hodgkin lymphoma (HL) cells by the Epstein-Barr virus (EBV) oncogene latent membrane protein-1 (LMP1) and that this up-regulation is mediated by NF-kappaB signaling. We also show that Bmi-1 is up-regulated by NF-kappaB in EBV-negative HL cells. Down-regulation of LMP1 and Bmi-1 decreased the survival of HL cells, suggesting that Bmi-1 may mediate the prosurvival effects of LMP1-induced NF-kappaB signaling in HL cells. Transcriptional targets of Bmi-1 were identified after its knockdown in an HL cell line. We show here that Bmi-1 and LMP1 down-regulate the ataxia telangiectasia-mutated (ATM) tumor suppressor and conclude that Bmi-1 contributes to LMP1-induced oncogenesis in HL.
Asunto(s)
Regulación Neoplásica de la Expresión Génica , Herpesvirus Humano 4/metabolismo , Enfermedad de Hodgkin/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Represoras/metabolismo , Proteínas de la Matriz Viral/metabolismo , Proteínas de la Ataxia Telangiectasia Mutada , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Línea Celular , Supervivencia Celular , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Regulación hacia Abajo , Perfilación de la Expresión Génica , Enfermedad de Hodgkin/genética , Enfermedad de Hodgkin/patología , Humanos , FN-kappa B/metabolismo , Proteínas Nucleares/genética , Complejo Represivo Polycomb 1 , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/genética , Proteínas Represoras/genética , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Regulación hacia Arriba , Proteínas de la Matriz Viral/genéticaRESUMEN
Protection from death receptor (DR)-mediated apoptosis has been proposed as an important step in the development of malignancy, enabling tumour cells not only to survive and escape antitumour immune responses, but also to develop resistance to chemotherapy or other cancer treatments. An important regulator of DR-induced death is the cellular FADD-like IL-1beta-converting enzyme inhibitory protein (c-FLIP) which, when overexpressed, can protect tumour cells from apoptosis. This review focuses on the role of c-FLIP as a tumour progression factor, with particular emphasis on recent work from the authors' laboratory concerning the contribution of c-FLIP to the pathogenesis of Hodgkin's lymphoma. The possibility of targeting c-FLIP as an approach to the treatment of cancer and, in particular, Hodgkin's lymphoma is discussed.
Asunto(s)
Enfermedad de Hodgkin/etiología , Enfermedad de Hodgkin/terapia , Péptidos y Proteínas de Señalización Intracelular/fisiología , Neoplasias/etiología , Neoplasias/terapia , Animales , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD , Progresión de la Enfermedad , Sistemas de Liberación de Medicamentos/métodos , Terapia Genética/métodos , Enfermedad de Hodgkin/genética , Enfermedad de Hodgkin/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Neoplasias/genética , Neoplasias/metabolismoRESUMEN
Hodgkin's lymphoma is one of the most common lymphoid cancers, particularly among young adults. Although there have been dramatic improvements in the treatment of Hodgkin's lymphoma, leading to high cure rates in some groups, current combination chemotherapy regimes are associated with significant secondary complications in long-term survivors. Furthermore, although a proportion of patients with Hodgkin's lymphoma will be cured, there still remains a significant rate of relapse and also a smaller proportion of poor responders who will go on to die of their disease. Therefore, developments in the treatment of Hodgkin's lymphoma must be directed at improving cure rates and reducing the burden of secondary complications. In recent years, the underlying pathogenesis of Hodgkin's lymphoma has become better understood. In particular, it is emerging that a key pathogenic event in Hodgkin's lymphoma is protection from Fas-induced cell death. Recent studies by the authors' group, and others, have demonstrated that this is, in part, due to the expression by Hodgkin/Reed-Sternberg cells of the cellular Fas-associated death domain-like IL-1 converting enzyme (FLICE)-like inhibitory protein molecule, a potent inhibitor of Fas-induced death. In this review, the role of cellular FLICE-like inhibitory protein in the pathogenesis of Hodgkin's lymphoma will be explored and also the possibility of targeting this molecule in order to provide an alternative and potentially safe approach to the treatment of Hodgkin's lymphoma will be investigated.
Asunto(s)
Apoptosis/fisiología , Enfermedad de Hodgkin/fisiopatología , Enfermedad de Hodgkin/terapia , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/fisiología , Antineoplásicos/farmacología , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD , Regulación hacia Abajo , Terapia Genética , Enfermedad de Hodgkin/genética , Humanos , Antígeno Ki-1/biosíntesis , Antígeno Ki-1/genética , Interferencia de ARN , ARN Interferente Pequeño , Receptores del Factor de Necrosis Tumoral , Receptor fasRESUMEN
The molecular mechanisms underlying the pathogenesis of the malignant Hodgkin's/Reed-Sternberg (HRS) cells of Hodgkin's lymphoma (HL) are largely unknown. This study investigates the contribution of phosphatidyl-inositide 3 kinase (PI3-kinase) and demonstrates that Akt, a substrate of PI3-kinase, is constitutively activated in HL-derived cell lines. Several downstream effectors of Akt signalling, including glycogen synthase kinase 3 (GSK-3) alpha and beta and mTOR substrates 4E-BP1 and p70 S6 kinase, were also phosphorylated in HL cells. The mTOR inhibitor, rapamycin, inhibited phosphorylation of these proteins. Furthermore, LY294002 inhibited phosphorylation of p70 S6 kinase and 4E-BP1, suggesting that the phosphorylation of p70 S6 kinase and 4E-BP1 in HL cells is PI3-kinase dependent. Importantly, HRS cells of primary tumour samples not only expressed high levels of activated Akt but also displayed phosphorylation of downstream targets of Akt activation including GSK-3, 4E-BP1, and p70 S6 Kinase. Inhibition of PI3-kinase and mTOR showed only modest effects on cell survival at the lower serum concentrations. However, rapamycin and doxorubicin acted synergistically to reduce HL cell survival. A combination of rapamycin and chemotherapy should be investigated in the treatment of HL.