RESUMEN
Multiple myeloma (MM) is a plasma cell cancer with poor survival, characterized by the expansion of multiple myeloma cells (MMCs) in the bone marrow. Using a microarray-based genome-wide screen for genes responding to DNA methyltransferases (DNMT) inhibition in MM cells, we identified RECQ1 among the most downregulated genes. RecQ helicases are DNA unwinding enzymes involved in the maintenance of chromosome stability. Here we show that RECQ1 is significantly overexpressed in MMCs compared to normal plasma cells and that increased RECQ1 expression is associated with poor prognosis in three independent cohorts of patients. Interestingly, RECQ1 knockdown inhibits cells growth and induces apoptosis in MMCs. Moreover, RECQ1 depletion promotes the development of DNA double-strand breaks, as evidenced by the formation of 53BP1 foci and the phosphorylation of ataxia-telangiectasia mutated (ATM) and histone variant H2A.X (H2AX). In contrast, RECQ1 overexpression protects MMCs from melphalan and bortezomib cytotoxicity. RECQ1 interacts with PARP1 in MMCs exposed to treatment and RECQ1 depletion sensitizes MMCs to poly(ADP-ribose) polymerase (PARP) inhibitor. DNMT inhibitor treatment results in RECQ1 downregulation through miR-203 deregulation in MMC. Altogether, these data suggest that association of DNA damaging agents and/or PARP inhibitors with DNMT inhibitors may represent a therapeutic approach in patients with high RECQ1 expression associated with a poor prognosis.
Asunto(s)
ADN de Neoplasias/genética , Resistencia a Antineoplásicos/fisiología , Mieloma Múltiple/enzimología , Proteínas de Neoplasias/fisiología , RecQ Helicasas/fisiología , Bortezomib/farmacología , Ciclo Celular/efectos de los fármacos , Roturas del ADN de Doble Cadena , Daño del ADN , Metilación de ADN/efectos de los fármacos , Replicación del ADN/efectos de los fármacos , ADN de Neoplasias/metabolismo , ADN-Citosina Metilasas/antagonistas & inhibidores , Inducción Enzimática , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Regulación Neoplásica de la Expresión Génica , Humanos , Melfalán/farmacología , MicroARNs/genética , Terapia Molecular Dirigida , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/genética , Mieloma Múltiple/patología , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/genética , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/enzimología , Células Plasmáticas/efectos de los fármacos , Células Plasmáticas/enzimología , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/genética , RecQ Helicasas/antagonistas & inhibidores , RecQ Helicasas/genética , Células Tumorales CultivadasRESUMEN
Tissue and functional regeneration takes place in the body at various stages throughout life. However, bone, cartilage, tendons, blood vessels and cardiac muscle have a limited capacity for self repair and, after injury or disease, the regenerative ability of these adult tissues is often insufficient and leads to nonfunctional scar tissue. In this context, mesenchymal stem cells, which are adult multipotential progenitors of mesoderm cells (osteoblasts, chondrocytes, adipocytes and stroma cells), represent a major hope for tissue-engineered replacement and regenerative medicine. Furthermore, the autologous use of these cells prevents immunological responses against new tissues and the risks of disease transmission from donors, which are both common problems of organ transplantation. While the existence of mesenchymal stem cells is undisputed, many questions remain regarding their self-renewal and capacity to differentiate, their homogenous nature as a cell population throughout the body and their true potential in regenerative medicine. In this article, the proteomics studies carried out to characterize mesenchymal stem cells and to help understand their physiology are reviewed.