RESUMO
Ribosomal DNA (rDNA) consists of highly repeated sequences that are prone to incurring damage. Delays or failure of rDNA double-strand break (DSB) repair are deleterious, and can lead to rDNA transcriptional arrest, chromosomal translocations, genomic losses, and cell death. Here, we show that the zinc-finger transcription factor GLI1, a terminal effector of the Hedgehog (Hh) pathway, is required for the repair of rDNA DSBs. We found that GLI1 is activated in triple-negative breast cancer cells in response to ionizing radiation (IR) and localizes to rDNA sequences in response to both global DSBs generated by IR and site-specific DSBs in rDNA. Inhibiting GLI1 interferes with rDNA DSB repair and impacts RNA polymerase I activity and cell viability. Our findings tie Hh signaling to rDNA repair and this heretofore unknown function may be critically important in proliferating cancer cells.
Assuntos
DNA Ribossômico/genética , Proteínas Hedgehog/genética , RNA Polimerase I/genética , Neoplasias de Mama Triplo Negativas/radioterapia , Proteína GLI1 em Dedos de Zinco/genética , Proteínas de Ciclo Celular/genética , Nucléolo Celular/genética , Nucléolo Celular/efeitos da radiação , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/efeitos da radiação , Quebras de DNA de Cadeia Dupla/efeitos da radiação , Dano ao DNA/efeitos da radiação , Reparo do DNA/efeitos da radiação , DNA Ribossômico/efeitos da radiação , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/efeitos da radiação , Humanos , RNA Polimerase I/efeitos da radiação , Radiação Ionizante , Ribossomos/genética , Ribossomos/efeitos da radiação , Transdução de Sinais/efeitos da radiação , Transcrição Gênica/genética , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
Salivary duct carcinoma (SDC) is a rare and aggressive malignancy for which limited data exist to guide treatment decisions. With the advent of advanced molecular testing and tumor genomic profiling, clinicians now have the ability to identify potential therapeutic targets in difficult-to-treat cancers such as SDC. This report presents a male patient with widely metastatic SDC found on targeted next-generation sequencing to have a BRAF p.V600E mutation. He experienced a prolonged and robust response to first-line systemic chemotherapy with dabrafenib and trametinib. During his response interval, new data emerged to justify subsequent treatment with both an immune checkpoint inhibitor and androgen blockade after his disease progressed. To our knowledge, this is the first report of frontline BRAF-directed therapy eliciting a response in metastatic SDC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma/terapia , MAP Quinase Quinase Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias das Glândulas Salivares/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma/diagnóstico por imagem , Carcinoma/genética , Carcinoma/secundário , Quimiorradioterapia Adjuvante/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Esvaziamento Cervical/métodos , Cuidados Paliativos/métodos , Glândula Parótida/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Ductos Salivares/patologia , Ductos Salivares/cirurgia , Neoplasias das Glândulas Salivares/diagnóstico por imagem , Neoplasias das Glândulas Salivares/genética , Neoplasias das Glândulas Salivares/patologia , Resultado do TratamentoRESUMO
The treatment of cancer continues to evolve toward personalized therapies based on individual patient and tumor characteristics. Our successes and failures in adopting a precision-oncology approach have demonstrated the utmost importance in identifying the proper predictive biomarkers of response. Until recently, most biomarkers were identified using immunohistochemistry for protein expression or single-gene analysis to identify targetable alterations. With the rapid propagation of next-generation sequencing to evaluate tumor tissue and "liquid biopsies," identification of genomic biomarkers is now standard, particularly in non-small cell lung cancer, for which there is now an extensive catalog of biomarker-directed therapies with more anticipated to come. Despite these great strides, it has also become apparent that using genomic biomarkers alone will be insufficient, as it has been consistently shown that at least one-half of patients who undergo tumor genomic profiling have no actionable alteration. This is perhaps to be expected given the remarkable breadth of nongenetic factors that contribute to tumor initiation and progression. Some have proposed that the next logical step is to use transcriptome profiling to define new biomarkers of response to targeted agents. Recently, results from the WINTHER trial were published, specifically investigating the use of transcriptomics to improve match rates over genomic next-generation sequencing alone. In this review, we discuss the complexities of precision-oncology efforts and appraise the available evidence supporting the incorporation of transcriptomic data into the precision-oncology framework in the historical context of the development of biomarkers for directing cancer therapy.
Assuntos
Perfilação da Expressão Gênica , Oncologia , Neoplasias/genética , Medicina de Precisão , Transcriptoma , Biomarcadores Tumorais , Gerenciamento Clínico , Perfilação da Expressão Gênica/métodos , Humanos , Biópsia Líquida , Oncologia/métodos , Técnicas de Diagnóstico Molecular , Terapia de Alvo Molecular , Neoplasias/diagnóstico , Neoplasias/mortalidade , Neoplasias/terapia , Medicina de Precisão/métodosRESUMO
Cancer has long been known to histologically resemble developing embryonic tissue. Since this early observation, a mounting body of evidence suggests that cancer mimics or co-opts developmental processes to facilitate tumor initiation and progression. Programs important in both normal ontogenesis and cancer progression broadly fall into three domains: the lineage commitment of pluripotent stem cells, the appropriation of primordial mechanisms of cell motility and invasion, and the influence of multiple aspects of the microenvironment on the parenchyma. In this review we discuss how derangements in these developmental pathways drive cancer progression with a particular focus on how they have emerged as targets of novel treatment strategies.
Assuntos
Linhagem da Célula/genética , Transformação Celular Neoplásica/genética , Desenvolvimento Embrionário/genética , Neoplasias/genética , Diferenciação Celular/genética , Células-Tronco Embrionárias/metabolismo , Humanos , Neoplasias/patologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologiaRESUMO
TRIP6 is an adaptor protein that regulates cell motility and antiapoptotic signaling. Although it has been implicated in tumorigenesis, the underlying mechanism remains largely unknown. Here we provide evidence that TRIP6 promotes tumorigenesis by serving as a bridge to promote the recruitment of p27(KIP1) to AKT in the cytosol. TRIP6 regulates the membrane translocation and activation of AKT and facilitates AKT-mediated recognition and phosphorylation of p27(KIP1) specifically at T157, thereby promoting the cytosolic mislocalization of p27(KIP1). This is required for p27(KIP1) to enhance lysophosphatidic acid (LPA)-induced ovarian cancer cell migration. TRIP6 also promotes serum-induced reduction of nuclear p27(KIP1) expression levels through Skp2-dependent and -independent mechanisms. Consequently, knockdown of TRIP6 in glioblastoma or ovarian cancer xenografts restores nuclear p27(KIP1) expression and impairs tumor proliferation. As TRIP6 is upregulated in gliomas and its levels correlate with poor clinical outcomes in a dose-dependent manner, it may represent a novel prognostic marker and therapeutic target in gliomas.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Transformação Celular Neoplásica/genética , Inibidor de Quinase Dependente de Ciclina p27/genética , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Proteínas com Domínio LIM/genética , Proteínas com Domínio LIM/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , ATPases Associadas a Diversas Atividades Celulares , Animais , Processos de Crescimento Celular/fisiologia , Linhagem Celular Tumoral , Movimento Celular/genética , Núcleo Celular/genética , Núcleo Celular/metabolismo , Citosol/metabolismo , Feminino , Glioblastoma/genética , Glioblastoma/metabolismo , Glioma/genética , Glioma/metabolismo , Células HEK293 , Humanos , Proteínas com Homeodomínio LIM/genética , Proteínas com Homeodomínio LIM/metabolismo , Camundongos , Camundongos Nus , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Fosforilação , Complexo de Endopeptidases do Proteassoma , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Quinases Associadas a Fase S/genética , Proteínas Quinases Associadas a Fase S/metabolismo , Transplante Heterólogo , Regulação para Cima , Zixina/genética , Zixina/metabolismoRESUMO
Thyroid hormone receptor interacting protein 6 (TRIP6), also known as zyxin-related protein-1 (ZRP-1), is an adaptor protein that belongs to the zyxin family of LIM proteins. TRIP6 is primarily localized in the cytosol or focal adhesion plaques, and may associate with the actin cytoskeleton. Additionally, it is capable of shuttling to the nucleus to serve as a transcriptional coregulator. Structural and functional analyses have revealed that through multidomain-mediated protein-protein interactions, TRIP6 serves as a platform for the recruitment of a wide variety of signaling molecules involved in diverse cellular responses, such as actin cytoskeletal reorganization, cell adhesion and migration, antiapoptotic signaling, osteoclast sealing zone formation and transcriptional control. Although the physiological functions of TRIP6 remain largely unknown, it has been implicated in cancer progression and telomere protection. Together, these studies suggest that TRIP6 plays multifunctional roles in different cellular responses, and thus may represent a novel target for therapeutic intervention.
Assuntos
Actinas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas com Domínio LIM/metabolismo , Transdução de Sinais , Fatores de Transcrição/metabolismo , Ativação Transcricional , ATPases Associadas a Diversas Atividades Celulares , Proteínas Adaptadoras de Transdução de Sinal/química , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Apoptose , Proteína Tirosina Quinase CSK , Adesão Celular , Movimento Celular , Citoesqueleto/metabolismo , Adesões Focais/genética , Adesões Focais/metabolismo , Humanos , Proteínas com Domínio LIM/química , Proteínas com Domínio LIM/genética , Camundongos , NF-kappa B/genética , NF-kappa B/metabolismo , Osteoclastos/citologia , Osteoclastos/metabolismo , Complexo de Endopeptidases do Proteassoma , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Proteína Tirosina Fosfatase não Receptora Tipo 13/genética , Proteína Tirosina Fosfatase não Receptora Tipo 13/metabolismo , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Transdução de Sinais/genética , Telômero/química , Telômero/genética , Homeostase do Telômero/genética , Fatores de Transcrição/química , Fatores de Transcrição/genética , Quinases da Família srcRESUMO
The Fas/CD95 receptor mediates apoptosis but is also capable of triggering nonapoptotic signals. However, the mechanisms that selectively regulate these opposing effects are not yet fully understood. Here we demonstrate that the activation of Fas or stimulation with lysophosphatidic acid (LPA) induces cytoskeletal reorganization, leading to the association of Fas with actin stress fibers and the adaptor protein TRIP6. TRIP6 binds to the cytoplasmic juxtamembrane domain of Fas and interferes with the recruitment of FADD to Fas. Furthermore, through physical interactions with NF-κB p65, TRIP6 regulates nuclear translocation and the activation of NF-κB upon Fas activation or LPA stimulation. As a result, TRIP6 antagonizes Fas-induced apoptosis and further enhances the antiapoptotic effect of LPA in cells that express high levels of TRIP6. On the other hand, TRIP6 promotes Fas-mediated cell migration in apoptosis-resistant glioma cells. This effect is regulated via the Src-dependent phosphorylation of TRIP6 at Tyr-55. As TRIP6 is overexpressed in glioblastomas, this may have a significant impact on enhanced NF-κB activity, resistance to apoptosis, and Fas-mediated cell invasion in glioblastomas.