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1.
Nutrients ; 9(4)2017 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-28346394

RESUMO

BACKGROUND/AIMS: Pancreatic cancer (PC) is ranked as the fourth leading cause of cancer-related deaths worldwide. Despite recent advances in treatment options, a modest impact on the outcome of the disease is observed so far. We have previously demonstrated that short-term fasting cycles have the potential to improve the efficacy of chemotherapy against PC. The aim of this study was to assess the effect of an engineered resistant-starch (ERS) mimicking diet on the growth of cancer cell lines in vitro, on the composition of fecal microbiota, and on tumor growth in an in vivo pancreatic cancer mouse xenograft model. MATERIALS AND METHODS: BxPC-3, MIA PaCa-2 and PANC-1 cells were cultured in the control, and in the ERS-mimicking diet culturing condition, to evaluate tumor growth and proliferation pathways. Pancreatic cancer xenograft mice were subjected to an ERS diet to assess tumor volume and weight as compared to mice fed with a control diet. The composition and activity of fecal microbiota were further analyzed in growth experiments by isothermal microcalorimetry. RESULTS: Pancreatic cancer cells cultured in an ERS diet-mimicking medium showed decreased levels of phospho-ERK1/2 (extracellular signal-regulated kinase proteins) and phospho-mTOR (mammalian target of rapamycin) levels, as compared to those cultured in standard medium. Consistently, xenograft pancreatic cancer mice subjected to an ERS diet displayed significant retardation in tumor growth. In in vitro growth experiments, the fecal microbial cultures from mice fed with an ERS diet showed enhanced growth on residual substrates, higher production of formate and lactate, and decreased amounts of propionate, compared to fecal microbiota from mice fed with the control diet. CONCLUSION: A positive effect of the ERS diet on composition and metabolism of mouse fecal microbiota shown in vitro is associated with the decrease of tumor progression in the in vivo PC xenograft mouse model. These results suggest that engineered dietary interventions could be supportive as a synergistic approach to enhance the efficacy of existing cancer treatments in pancreatic cancer patients.


Assuntos
Colo/microbiologia , Dieta , Microbioma Gastrointestinal , Neoplasias Pancreáticas/dietoterapia , Amido/administração & dosagem , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA Bacteriano/isolamento & purificação , Modelos Animais de Doenças , Fezes/microbiologia , Feminino , Camundongos , Camundongos Nus , Proteínas Quinases Ativadas por Mitógeno , Amido/química , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Artigo em Inglês | MEDLINE | ID: mdl-26357277

RESUMO

Pancreatic cancer is a highly aggressive and chemotherapy-resistant malignant neoplasm. In basal condition, it is characterized by elevated autophagy activity, which is required for tumor growth and that correlates with treatment failure. We analyzed the expression of autophagy related genes in different pancreatic cancer cell lines. A correlation-based network analysis evidenced the sociality and topological roles of the autophagy-related genes after serum starvation. Structural and functional tests identified a core set of autophagy related genes, suggesting different scenarios of autophagic responses to starvation, which may be responsible for the clinical variations associated with pancreatic cancer pathogenesis.


Assuntos
Autofagia/genética , Homeostase/genética , Neoplasias Pancreáticas/genética , Linhagem Celular Tumoral , Análise por Conglomerados , Biologia Computacional , Perfilação da Expressão Gênica , Humanos
3.
Oncotarget ; 6(21): 18545-57, 2015 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-26176887

RESUMO

BACKGROUND/AIMS: Pancreatic cancer (PC) is ranked as the fourth leading cause of cancer-related deaths worldwide. Despite recent advances in treatment options, a modest impact on the outcome of the disease is observed so far. Short-term fasting cycles have been shown to potentiate the efficacy of chemotherapy against glioma. The aim of this study was to assess the effect of fasting cycles on the efficacy of gemcitabine, a standard treatment for PC patients, in vitro and in an in vivo pancreatic cancer mouse xenograft model. MATERIALS AND METHODS: BxPC-3, MiaPaca-2 and Panc-1 cells were cultured in standard and fasting mimicking culturing condition to evaluate the effects of gemcitabine. Pancreatic cancer xenograft mice were subjected to 24h starvation prior to gemcitabine injection to assess the tumor volume and weight as compared to mice fed ad libitum. RESULTS: Fasted pancreatic cancer cells showed increased levels of equilibrative nucleoside transporter (hENT1), the transporter of gemcitabine across the cell membrane, and decreased ribonucleotide reductase M1 (RRM1) levels as compared to those cultured in standard medium. Gemcitabine was more effective in inducing cell death on fasted cells as compared to controls. Consistently, xenograft pancreatic cancer mice subjected to fasting cycles prior to gemcitabine injection displayed a decrease of more than 40% in tumor growth. CONCLUSIONS: Fasting cycles enhance gemcitabine effect in vitro and in the in vivo PC xenograft mouse model. These results suggest that restrictive dietary interventions could enhance the efficacy of existing cancer treatments in pancreatic cancer patients.


Assuntos
Desoxicitidina/análogos & derivados , Jejum , Neoplasias Pancreáticas/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Antimetabólitos Antineoplásicos/farmacologia , Bovinos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Meios de Cultura/química , Meios de Cultura/farmacologia , Desoxicitidina/farmacologia , Transportador Equilibrativo 1 de Nucleosídeo/genética , Transportador Equilibrativo 1 de Nucleosídeo/metabolismo , Feminino , Sangue Fetal/química , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Immunoblotting , Camundongos Nus , Microscopia de Fluorescência , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ribonucleosídeo Difosfato Redutase , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Gencitabina
4.
Chronobiol Int ; 32(4): 497-512, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25798752

RESUMO

Pancreatic cancer (PC), the fourth leading cause of cancer-related deaths, is characterized by high aggressiveness and resistance to chemotherapy. Pancreatic carcinogenesis is kept going by derangement of essential cell processes, such as proliferation, apoptosis, metabolism and autophagy, characterized by rhythmic variations with 24-h periodicity driven by the biological clock. We assessed the expression of the circadian genes ARNLT, ARNLT2, CLOCK, PER1, PER2, PER3, CRY1, CRY2 and the starvation-activated histone/protein deacetylase SIRT1 in 34 matched tumor and non-tumor tissue specimens of PC patients, and evaluated in PC derived cell lines if the modulation of SIRT1 expression through starvation could influence the temporal pattern of expression of the circadian genes. We found a significant down-regulation of ARNLT (p = 0.015), CRY1 (p = 0.013), CRY2 (p = 0.001), PER1 (p < 0.0001), PER2 (p < 0.001), PER3 (p = 0.001) and SIRT1 (p = 0.017) in PC specimens. PER3 and CRY2 expression levels were lower in patients with jaundice at diagnosis ( < 0.05). Having adjusted for age, adjuvant therapy and tumor stage, we evidenced that patients with higher PER2 and lower SIRT1 expression levels showed lower mortality (p = 0.028). Levels and temporal patterns of expression of many circadian genes and SIRT1 significantly changed upon serum starvation in vitro, with differences among four different PC cell lines examined (BXPC3, CFPAC, MIA-PaCa-2 and PANC-1). Serum deprivation induced changes of the overall mean level of the wave and amplitude, lengthened or shortened the cycle time and phase-advanced or phase-delayed the rhythmic oscillation depending on the gene and the PC cell line examined. In conclusion, a severe deregulation of expression of SIRT1 and circadian genes was evidenced in the cancer specimens of PC patients, and starvation influenced gene expression in PC cell lines, suggesting that the altered interplay between SIRT1 and the core circadian proteins could represent a crucial player in the process of pancreatic carcinogenesis.


Assuntos
Adenocarcinoma/genética , Proteínas CLOCK/genética , Ritmo Circadiano/genética , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Pancreáticas/genética , Sirtuína 1/genética , Idoso , Proteínas CLOCK/metabolismo , Ritmo Circadiano/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
5.
Cancer Lett ; 353(1): 41-51, 2014 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-25038272

RESUMO

Bcl-6 translocation is a genetic alteration that is commonly detected in Primary Central Nervous System Lymphoma. The role of this protein in cerebral tumors is unclear. In this study we investigated Bcl-6 translocation and its transcriptional and translational levels in formalin-fixed, paraffin-embedded cerebral tissue sections from glioblastoma (GBM), low-grade glioma (Astrocytoma grade II and III), and meningioma patients, and correlated them with apoptotic processes and p53 and caspase-3 expression. The results showed a frequency of 36.6% of Bcl-6 translocation in GBM patients and a decreased expression in low-grade glioma patients, correlated with the severity of the disease. Bcl-6 translocation induced an overexpression of both Bcl-6 protein and messenger in GBM, inhibiting apoptotic processes and caspases 3 expression. On the contrary, in low-grade gliomas and meningiomas Bcl-6 expression was reduced, resulting in an increase of apoptotic processes. Finally, p53 expression levels in brain tumors were comparable to Bcl-6 levels. Overall, these data demonstrate, for the first time, that the Bcl-6 gene translocates in GBM patients and that its translocation and expression are correlated with apoptosis inhibition, indicating a key role for this gene in the control of cellular proliferation. This study offers further insights into glioblastoma biology, and supports Bcl-6 as a new diagnostic marker to evaluate the disease severity.


Assuntos
Biomarcadores Tumorais/genética , Proteínas de Ligação a DNA/genética , Glioblastoma/genética , Translocação Genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose , Biomarcadores Tumorais/análise , Neoplasias Encefálicas/química , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Caspase 3/análise , Proliferação de Células , Proteínas de Ligação a DNA/análise , Feminino , Regulação Neoplásica da Expressão Gênica , Glioblastoma/química , Glioblastoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-bcl-6 , RNA Mensageiro/análise , Estudos Retrospectivos , Proteína Supressora de Tumor p53/análise
6.
Tumour Biol ; 35(8): 7307-15, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24833096

RESUMO

Hepatocellular carcinoma is the fifth most common tumor and the third cause of death for cancer in the world. Among the main causative agents of this tumor is the chronic infection by hepatitis viruses B and C, which establish a context of chronic inflammation degenerating in fibrosis, cirrhosis, and, finally, cancer. Recent findings, however, indicate that hepatitis viruses are not only responsible for cancer onset but also for its progression towards metastasis. Indeed, they are able to promote epithelial-mesenchymal transition, a process of cellular reprogramming underlying tumor spread. In this manuscript, we review the currently known molecular mechanisms by which hepatitis viruses induce epithelial-mesenchymal transition and, thus, hepatocellular carcinoma progression.


Assuntos
Carcinoma Hepatocelular/etiologia , Transição Epitelial-Mesenquimal , Hepatite Viral Humana/complicações , Neoplasias Hepáticas/etiologia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Progressão da Doença , Hepatite B/complicações , Hepatite C/complicações , Hepatite D/complicações , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia
7.
PLoS One ; 9(3): e89505, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24657938

RESUMO

OBJECTIVES: Emerging evidence suggests that maternal obesity (MO) predisposes offspring to obesity and the recently described non-alcoholic fatty pancreas disease (NAFPD) but involved mechanisms remain unclear. Using a pathophysiologically relevant murine model, we here investigated a role for the biological clock--molecular core circadian genes (CCG) in the generation of NAFPD. DESIGN: Female C57BL6 mice were fed an obesogenic diet (OD) or standard chow (SC) for 6 weeks, prior to pregnancy and throughout gestation and lactation: resulting offspring were subsequently weaned onto either OD (Ob_Ob and Con_Ob) or standard chow (Ob_Con and Con_Con) for 6 months. Biochemical, pro-inflammatory and pro-fibrogenic markers associated with NAFPD were then evaluated and CCG mRNA expression in the pancreas determined. RESULTS: Offspring of obese dams weaned on to OD (Ob_Ob) had significantly increased (p≤0.05): bodyweight, pancreatic triglycerides, macrovesicular pancreatic fatty-infiltration, and pancreatic mRNA expression of TNF-α, IL-6, α-SMA, TGF-ß and increased collagen compared to offspring of control dams weaned on to control chow (Con_Con). Analyses of CCG expression demonstrated a phase shift in CLOCK (-4.818, p<0.01), REV-ERB-α (-1.4,p<0.05) and Per2 (3.27,p<0.05) in association with decreased amplitude in BMAL-1 (-0.914,p<0.05) and PER2 (1.18,p<0.005) in Ob_Ob compared to Con_Con. 2-way ANOVA revealed significant interaction between MO and post-weaning OD in expression of CLOCK (p<0.005), PER1 (p<0.005) and PER2 (p<0.05) whilst MO alone influenced the observed rhythmic variance in expression of all 5 measured CCG. CONCLUSIONS: Fetal and neonatal exposure to a maternal obesogenic environment interacts with a post-natal hyper-calorific environment to induce offspring NAFPD through mechanisms involving perturbations in CCG expression.


Assuntos
Ritmo Circadiano , Pancreatopatias/etiologia , Efeitos Tardios da Exposição Pré-Natal , Análise de Variância , Animais , Peso Corporal , Proteínas CLOCK/genética , Proteínas CLOCK/metabolismo , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Camundongos Endogâmicos C57BL , Pancreatopatias/patologia , Gravidez , RNA Mensageiro/metabolismo
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