RESUMO
Cancer and the immune system share an intimate relationship. Chronic inflammation increases the risk of cancer occurrence and can also drive inflammatory mediators into the tumor microenvironment enhancing tumor growth and survival. The p38 MAPK pathway is activated both acutely and chronically by stress, inflammatory chemokines, chronic inflammatory conditions, and cancer. These properties have led to extensive efforts to find effective drugs targeting p38, which have been unsuccessful. The immediate downstream serine/threonine kinase and substrate of p38 MAPK, mitogen-activated-protein-kinase-activated-protein-kinase-2 (MK2) protects cells against stressors by regulating the DNA damage response, transcription, protein and messenger RNA stability, and motility. The phosphorylation of downstream substrates by MK2 increases inflammatory cytokine production, drives an immune response, and contributes to wound healing. By binding directly to p38 MAPK, MK2 is responsible for the export of p38 MAPK from the nucleus which gives MK2 properties that make it unique among the large number of p38 MAPK substrates. Many of the substrates of both p38 MAPK and MK2 are separated between the cytosol and nucleus and interfering with MK2 and altering this intracellular translocation has implications for the actions of both p38 MAPK and MK2. The inhibition of MK2 has shown promise in combination with both chemotherapy and radiotherapy as a method for controlling cancer growth and metastasis in a variety of cancers. Whereas the current data are encouraging the field requires the development of selective and well tolerated drugs to target MK2 and a better understanding of its effects for effective clinical use.
Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias , Proteínas Serina-Treonina Quinases/metabolismo , Sobrevivência Celular , Humanos , Sistema de Sinalização das MAP Quinases , Microambiente Tumoral , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Intracellular pathogens have evolved to utilize normal cellular processes to complete their replicative cycles. Pathogens that interface with proliferative cell signaling pathways risk infections that can lead to cancers, but the factors that influence malignant outcomes are incompletely understood. Human papillomaviruses (HPVs) predominantly cause benign hyperplasia in stratifying epithelial tissues. However, a subset of carcinogenic or "high-risk" HPV (hr-HPV) genotypes are etiologically linked to nearly 5% of all human cancers. Progression of hr-HPV-induced lesions to malignancies is characterized by increased expression of the E6 and E7 oncogenes and the oncogenic functions of these viral proteins have been widely studied. Yet, the mechanisms that regulate hr-HPV oncogene transcription and suppress their expression in benign lesions remain poorly understood. Here, we demonstrate that EGFR/MEK/ERK signaling, influenced by epithelial contact inhibition and tissue differentiation cues, regulates hr-HPV oncogene expression. Using monolayer cells, epithelial organotypic tissue models, and neoplastic tissue biopsy materials, we show that cell-extrinsic activation of ERK overrides cellular control to promote HPV oncogene expression and the neoplastic phenotype. Our data suggest that HPVs are adapted to use the EGFR/MEK/ERK signaling pathway to regulate their productive replicative cycles. Mechanistic studies show that EGFR/MEK/ERK signaling influences AP-1 transcription factor activity and AP-1 factor knockdown reduces oncogene transcription. Furthermore, pharmacological inhibitors of EGFR, MEK, and ERK signaling quash HPV oncogene expression and the neoplastic phenotype, revealing a potential clinical strategy to suppress uncontrolled cell proliferation, reduce oncogene expression and treat HPV neoplasia.
Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Proteínas Oncogênicas Virais/metabolismo , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/complicações , Neoplasias do Colo do Útero/virologia , MAP Quinases Reguladas por Sinal Extracelular/genética , Feminino , Perfilação da Expressão Gênica , Humanos , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Terapia de Alvo Molecular , Proteínas Oncogênicas Virais/genética , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/metabolismo , Infecções por Papillomavirus/virologia , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/terapiaRESUMO
Radiation therapy (RT) is a cornerstone of treatment in the management of head and neck squamous cell carcinomas (HNSCC), yet treatment failure and disease recurrence are common. The p38/MK2 pathway is activated in response to cellular stressors, including radiation, and promotes tumor inflammation in a variety of cancers. We investigated MK2 pathway activation in HNSCC and the interaction of MK2 and RT in vitro and in vivo. We used a combination of an oropharyngeal SCC tissue microarray, HNSCC cell lines, and patient-derived xenograft (PDX) tumor models to study the effect of RT on MK2 pathway activation and to determine how inhibition of MK2 by pharmacologic (PF-3644022) and genetic (siRNA) methods impacts tumor growth. We show that high phosphorylated MK2 (p-MK2) levels are associated with worsened disease-specific survival in p16-negative HNSCC patients. RT increased p-MK2 in both p16-positive, HPV-positive and p16-negative, HPV-negative HNSCC cell lines. Pharmacologic inhibition or gene silencing of MK2 in vitro abrogated RT-induced increases in p-MK2; inflammatory cytokine expression and expression of the downstream MK2 target, heat shock protein 27 (HSP27); and markers of epithelial-to-mesenchymal transition. Mouse PDX models treated with a combination of RT and MK2 inhibitor experienced decreased tumor growth and increased survival. Our results suggest that MK2 is a potential prognostic biomarker for head and neck cancer and that MK2 pathway activation can mediate radiation resistance in HNSCC.
Assuntos
Citocinas/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Infecções por Papillomavirus/complicações , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Radioterapia/métodos , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Animais , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proliferação de Células , Transição Epitelial-Mesenquimal , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/radioterapia , Neoplasias de Cabeça e Pescoço/virologia , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Camundongos Nus , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/virologia , Fosforilação , Prognóstico , Proteínas Serina-Treonina Quinases/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Colorectal cancer (CRC) development and progression is associated with chronic inflammation. We have identified the MAPK-activated protein kinase 2 (MK2) pathway as a primary mediator of inflammation in CRC. MK2 signaling promotes production of proinflammatory cytokines IL-1ß, IL-6 and TNF-α. These cytokines have been implicated in tumor growth, invasion and metastasis. For the first time, we investigate whether MK2 inhibition can improve outcome in two mouse models of CRC. In our azoxymethane/dextran sodium sulfate (AOM/DSS) model of colitis-associated CRC, MK2 inhibitor treatment eliminated murine tumor development. Using the implanted, syngeneic murine CRC cell line CT26, we observe significant tumor volume reduction following MK2 inhibition. Tumor cells treated with MK2 inhibitors produced 80% less IL-1ß, IL-6 and TNF-α and demonstrated decreased invasion. Replenishment of downstream proinflammatory MK2-mediated cytokines (IL-1ß, IL-6 and TNF-α) to tumors led to restoration of tumor proliferation and rapid tumor regrowth. These results demonstrate the importance of MK2 in driving proinflammatory cytokine production, its relevance to in vivo tumor proliferation and invasion. Inhibition of MK2 may represent an attractive therapeutic target to suppress tumor growth and progression in patients.
Assuntos
Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Azoximetano/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Colite/induzido quimicamente , Colite/metabolismo , Colite/patologia , Neoplasias Colorretais/induzido quimicamente , Sulfato de Dextrana/farmacologia , Feminino , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Transdução de Sinais/fisiologiaRESUMO
BACKGROUND: Squamous cell carcinoma of the head and neck (HNSCC) represents an array of disease processes with a generally unfavorable prognosis. Inflammation plays an important role in tumor development and response to therapy. We performed a retrospective analysis of HNSCC patients to explore the relationship of the lymphocyte and neutrophil counts, the neutrophil-to-lymphocyte ratio (NLR) overall survival (OS), cancer-specific survival (CSS), local control (LC) and distant control (DC). MATERIALS/METHODS: All patients received definitive treatment for cancers of the oropharynx or larynx between 2006-2015. Neutrophil and lymphocyte counts were collected pre-, during-, and post-treatment. The correlations of patient, tumor, and biological factors to OS, CSS, LC and DC were assessed. RESULTS: 196 patients met our inclusion criteria; 171 patients were Stage III or IV. Median follow-up was 2.7 years. A higher neutrophil count at all treatment time points was predictive of poor OS with the pre-treatment neutrophil count and overall neutrophil nadir additionally predictive of DC. Higher pre-treatment and overall NLR correlated to worse OS and DC, respectively. CONCLUSION: A higher pre-treatment neutrophil count correlates to poor OS, CSS and DC. Lymphocyte counts were not found to impact survival or tumor control. Higher pre-treatment NLR is prognostic of poor OS.
Assuntos
Neoplasias Laríngeas/patologia , Neoplasias Laríngeas/radioterapia , Neutrófilos/patologia , Neoplasias Orofaríngeas/patologia , Neoplasias Orofaríngeas/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Laríngeas/sangue , Contagem de Linfócitos , Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Neoplasias Orofaríngeas/sangue , Prognóstico , Análise de SobrevidaRESUMO
Context: Accumulation of brain iron is linked to aging and protein-misfolding neurodegenerative diseases. High iron intake may influence important brain health outcomes in later life. Objective: The aim of this systematic review was to examine evidence from animal and human studies of the effects of high iron intake or peripheral iron status on adult cognition, brain aging, and neurodegeneration. Data Sources: MEDLINE, Scopus, CAB Abstracts, the Cochrane Central Register of Clinical Trials, and OpenGrey databases were searched. Study Selection: Studies investigating the effect of elevated iron intake at all postnatal life stages in mammalian models and humans on measures of adult brain health were included. Data Extraction: Data were extracted and evaluated by two authors independently, with discrepancies resolved by discussion. Neurodegenerative disease diagnosis and/or behavioral/cognitive, biochemical, and brain morphologic findings were used to study the effects of iron intake or peripheral iron status on brain health. Risk of bias was assessed for animal and human studies. PRISMA guidelines for reporting systematic reviews were followed. Results: Thirty-four preclinical and 14 clinical studies were identified from database searches. Thirty-three preclinical studies provided evidence supporting an adverse effect of nutritionally relevant high iron intake in neonates on brain-health-related outcomes in adults. Human studies varied considerably in design, quality, and findings; none investigated the effects of high iron intake in neonates/infants. Conclusions: Human studies are needed to verify whether dietary iron intake levels used in neonates/infants to prevent iron deficiency have effects on brain aging and neurodegenerative disease outcomes.
Assuntos
Envelhecimento/efeitos dos fármacos , Cognição/efeitos dos fármacos , Ferro da Dieta/administração & dosagem , Ferro da Dieta/efeitos adversos , Anemia Ferropriva/sangue , Anemia Ferropriva/tratamento farmacológico , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Bases de Dados Factuais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Humanos , Ferro/sangue , Deficiências de Ferro , Metanálise como Assunto , Estado Nutricional , Estudos Observacionais como Assunto , Viés de Publicação , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de RiscoRESUMO
BACKGROUND: Dysregulation of iron homeostasis is implicated in the pathogenesis of Huntington's disease. We have previously shown that increased iron intake in R6/2 HD neonatal mice, but not adult R6/2 HD mice potentiates disease outcomes at 12-weeks of age corresponding to advanced HD [Redox Biol. 2015;4â:â363-74]. However, whether these findings extend to other HD models is unknown. In particular, it is unclear if increased neonatal iron intake can promote neurodegeneration in mouse HD models where disease onset is delayed to mid-adult life. OBJECTIVE: To determine if increased dietary iron intake in neonatal and adult life-stages potentiates HD in the slowly progressive YAC128 HD mouse model. METHODS: Female neonatal mice were supplemented daily from days 10-17 with 120µg/g body weight of carbonyl iron. Adult mice were provided diets containing low (50âppm), medium (150âppm) and high (500âppm) iron concentrations from 2-months of age. HD progression was determined using behavioral, brain morphometric and biochemical approaches. RESULTS: Neonatal-iron supplemented YAC128 HD mice had significantly lower striatal volumes and striatal neuronal cell body volumes as compared to control HD mice at 1-year of age. Neonatal-iron supplementation of HD mice had no effect on rota-rod motor endurance and brain iron or glutathione status. Adult iron intake level had no effect on HD progression. YAC128 HD mice had altered peripheral responses to iron intake compared to iron-matched wild-type controls. CONCLUSIONS: Female YAC128 HD mice supplemented with nutritionally-relevant levels of iron as neonates demonstrate increased striatal degeneration 1-year later.
Assuntos
Corpo Estriado/efeitos dos fármacos , Doença de Huntington/metabolismo , Ferro da Dieta/efeitos adversos , Ferro da Dieta/metabolismo , Animais , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/patologia , Modelos Animais de Doenças , Feminino , Histocitoquímica , Ferro da Dieta/administração & dosagem , CamundongosRESUMO
Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a CAG repeat expansion that encodes a polyglutamine tract in huntingtin (htt) protein. Dysregulation of brain iron homeostasis, oxidative stress and neurodegeneration are consistent features of the HD phenotype. Therefore, environmental factors that exacerbate oxidative stress and iron dysregulation may potentiate HD. Iron supplementation in the human population is common during infant and adult-life stages. In this study, iron supplementation in neonatal HD mice resulted in deterioration of spontaneous motor running activity, elevated levels of brain lactate and oxidized glutathione consistent with increased energetic dysfunction and oxidative stress, and increased striatal and motor cortical neuronal atrophy, collectively demonstrating potentiation of the disease phenotype. Oxidative stress, energetic, and anatomic markers of degeneration were not affected in wild-type littermate iron-supplemented mice. Further, there was no effect of elevated iron intake on disease outcomes in adult HD mice. We have demonstrated an interaction between the mutant huntingtin gene and iron supplementation in neonatal HD mice. Findings indicate that elevated neonatal iron intake potentiates mouse HD and promotes oxidative stress and energetic dysfunction in brain. Neonatal-infant dietary iron intake level may be an environmental modifier of human HD.