RESUMO
While clinical benefit of the proteasome inhibitor (PI) bortezomib (BTZ) for multiple myeloma (MM) patients remains unchallenged, dose-limiting toxicities and drug resistance limit the long-term utility. The E3 ubiquitin ligase Skp1-Cullin-1-Skp2 (SCFSkp2) promotes proteasomal degradation of the cell cycle inhibitor p27 to enhance tumor growth. Increased SKP2 expression and reduced p27 levels are frequent in human cancers and are associated with therapeutic resistance. SCFSkp2 activity is increased by the Cullin-1-binding protein Commd1 and the Skp2-binding protein Cks1B. Here we observed higher CUL1, COMMD1 and SKP2 mRNA levels in CD138+ cells isolated from BTZ-resistant MM patients. Higher CUL1, COMMD1, SKP2 and CKS1B mRNA levels in patient CD138+ cells correlated with decreased progression-free and overall survival. Genetic knockdown of CUL1, COMMD1 or SKP2 disrupted the SCFSkp2 complex, stabilized p27 and increased the number of annexin-V-positive cells after BTZ treatment. Chemical library screens identified a novel compound, designated DT204, that reduced Skp2 binding to Cullin-1 and Commd1, and synergistically enhanced BTZ-induced apoptosis. DT204 co-treatment with BTZ overcame drug resistance and reduced the in vivo growth of myeloma tumors in murine models with survival benefit. Taken together, the results provide proof of concept for rationally designed drug combinations that incorporate SCFSkp2 inhibitors to treat BTZ resistant disease.
Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Farmacogenética , Proteínas Quinases Associadas a Fase S/metabolismo , Bibliotecas de Moléculas Pequenas , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Proteínas Culina/genética , Modelos Animais de Doenças , Descoberta de Drogas , Sinergismo Farmacológico , Feminino , Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Farmacogenética/métodos , Prognóstico , Inibidores de Proteassoma/farmacologia , Proteínas Quinases Associadas a Fase S/antagonistas & inibidores , Proteínas Quinases Associadas a Fase S/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Eosinophilic esophagitis (EoE) is an allergic inflammatory disorder of the esophagus that is compounded by genetic predisposition and hypersensitivity to environmental antigens. Using high-density oligonucleotide expression chips, a disease-specific esophageal transcript signature was identified and was shown to be largely reversible with therapy. In an effort to expand the molecular signature of EoE, we performed RNA sequencing on esophageal biopsies from healthy controls and patients with active EoE and identified a total of 1607 significantly dysregulated transcripts (1096 upregulated, 511 downregulated). When clustered by raw expression levels, an abundance of immune cell-specific transcripts are highly induced in EoE but expressed at low (or undetectable) levels in healthy controls. Moreover, 66% of the gene signature identified by RNA sequencing was previously unrecognized in the EoE transcript signature by microarray-based expression profiling and included several long non-coding RNAs (lncRNA), an emerging class of transcriptional regulators. The lncRNA BRAF-activated non-protein coding RNA (BANCR) was upregulated in EoE and induced in interleukin-13 (IL-13)-treated primary esophageal epithelial cells. Repression of BANCR significantly altered the expression of IL-13-induced proinflammatory genes. Together, these data comprise new potential biomarkers of EoE and demonstrate a novel role for lncRNAs in EoE and IL-13-associated responses.
Assuntos
Esofagite Eosinofílica/genética , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Análise de Sequência de RNA/métodos , Transcriptoma , Linhagem Celular , Células Cultivadas , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Interleucina-13/farmacologia , Interferência de RNA , RNA não Traduzido/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Regulação para CimaRESUMO
BACKGROUND: Metabolic syndrome, a constellation of risk factors associated with cardiovascular disease and Type 2 diabetes, has reached epidemic proportions worldwide. Epidemiological studies in transitional societies will provide insight into the underlying factors that interact in its manifestation. AIMS: To estimate the prevalence of metabolic syndrome, provide a comparative analysis of two metabolic syndrome definitions and assess clustering and association of metabolic traits and cardiovascular diseases in an Adriatic island population. SUBJECTS AND METHODS: In a cross-sectional study, data on four anthropometric, blood pressure and 11 biochemical traits were obtained from 1430 adults from the island of Hvar. RESULTS: Prevalence of metabolic syndrome was 25% and 38.5% based on Adult Treatment Panel III and International Diabetes Federation definitions, respectively. Rates of abdominal obesity, elevated blood glucose and hypertension were high. Among the traits not included in the definitions, levels of LDL, total cholesterol and fibrinogen were markedly elevated. The majority of the phenotypes were significantly associated with the syndrome, the strongest being waist circumference. CONCLUSION: The Croatian islanders are characterized by a high prevalence of metabolic abnormalities. Central obesity is the strongest contributor of the syndrome. With a high prevalence of dyslipidemia and pro-inflammatory factors, the population is at substantial risk for cardiovascular diseases.
