RESUMEN
Head and neck cancer (HNC), which is among the deadliest malignancies, is the seventh most common cancer worldwide. How cholesterol homeostasis is linked to human cancers has long been a source of curiosity. One of the few proteins that are involved in cholesterol homeostasis is ATP-binding cassette transporter A1 (ABCA1), which is broadly expressed in numerous tissues. ABCA1 increases cholesterol efflux, inhibits cholesterol deposition in cells, and modulates anticancer activities. Therefore, it is not surprising that decreased ABCA1 activity and altered cholesterol homeostasis are implicated in the patho-physiology of HNCs. In this review, we focus on the role of cholesterol metabolism in the patho-physiology and progression of HNCs, with an emphasis on biological effects of ABCA1 transporters. We also review therapeutic approaches targeting cholesterol metabolism, as well as how combining such approaches with existing anticancer treatments may have synergistic effects and therefore open up new therapeutic avenues.
Asunto(s)
Transportador 1 de Casete de Unión a ATP , Neoplasias de Cabeza y Cuello , Humanos , Transportador 1 de Casete de Unión a ATP/metabolismo , Colesterol/metabolismoRESUMEN
Prostate cancer is the most frequently diagnosed tumor in men and the second leading cause of cancer-associated mortality in most developed countries. 3,5-Diaryl substituted pyrazole derivatives (20-28) were prepared starting from related chalcones and biologically evaluated for in vitro growth inhibition activity against PC3 and DU145 human prostate cancer cell lines. Compounds 23, 26, and 28 were found to be more potent as compared to the other halogen-substituted derivatives. Especially, the 2-bromo-substituted pyrazole derivative (26) was found to be more potent against PC3 and DU145 cells. Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor 2 (VEGFR2) are known to be expressed in DU145 and PC3 cancer cells. The binding mode of the most selective compound 26 toward EGFR and VEGFR2 was investigated by employing docking simulations based on GLIDE standard precision (-5.912 and -6.949 kcal/mol, respectively).
Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Pirazoles/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Receptores ErbB/metabolismo , Humanos , Masculino , Simulación del Acoplamiento Molecular , Células PC-3 , Neoplasias de la Próstata/patología , Pirazoles/síntesis química , Pirazoles/química , Relación Estructura-Actividad , Receptor 2 de Factores de Crecimiento Endotelial VascularRESUMEN
BACKGROUND: Prostate cancer (PCa) is the most commonly diagnosed malignancy in men who are especially over the age of 50 years in the western countries. Currently used therapeutic modalities mostly fail to give positive clinical outcomes and nearly 30% of the PCa patients eventually develop clinical recurrence. Therefore, understanding the underlying mechanisms of PCa progression is of paramount importance to help determining the course of disease. In this study, we aimed at profiling the differentially expressed microRNAs in recurrent PCa samples. METHODS: We profiled the microRNA expression of 20 recurrent and 20 non-recurrent PCa patients with microRNA microarray, and validated the differential expression of significantly deregulated microRNAs in 40 recurrent and 39 non-recurrent PCa specimens using quantitative reverse-transcription PCR (qRT-PCR). Data were statistically analyzed using two-sided Student's t-test, Pearson Correlation test, Receiver operating characteristic (ROC) analysis. RESULTS: Our results demonstrated that a total of 682 probes were significantly deregulated in recurrent versus non-recurrent PCa specimen comparison. Among those, we confirmed the significant downregulation of miR-424 and upregulation of miR-572 with further qRT-PCR analysis in a larger sample set. Further ROC analysis showed that these microRNAs have enough power to distinguish recurrent specimens from non-recurrent ones on their own. CONCLUSIONS: Here, we report that differential expression of miR-424 and miR-572 in recurrent PCa specimens can serve as novel biomarkers for prediction of PCa progression.
Asunto(s)
MicroARNs/biosíntesis , MicroARNs/genética , Recurrencia Local de Neoplasia/genética , Neoplasias de la Próstata/genética , Biomarcadores de Tumor/biosíntesis , Biomarcadores de Tumor/genética , Estudios de Cohortes , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Pronóstico , Prostatectomía , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/cirugía , ARN Neoplásico/genética , ARN Neoplásico/metabolismoRESUMEN
POC1A encodes a WD repeat protein localizing to centrioles and spindle poles and is associated with short stature, onychodysplasia, facial dysmorphism and hypotrichosis (SOFT) syndrome. These main features are related to the defect in cell proliferation of chondrocytes in growth plate. In the current study, we aimed at identifying the molecular basis of two patients with primordial dwarfism (PD) in a single family through utilization of whole-exome sequencing. A novel homozygous p.T120A missense mutation was detected in POC1A in both patients, a known causative gene of SOFT syndrome, and confirmed using Sanger sequencing. To test the pathogenicity of the detected mutation, primary fibroblast cultures obtained from the patients and a control individual were used. For evaluating the global gene expression profile of cells carrying p.T120A mutation in POC1A, we performed the gene expression array and compared their expression profiles to those of control fibroblast cells. The gene expression array analysis showed that 4800 transcript probes were significantly deregulated in cells with p.T120A mutation in comparison to the control. GO term association results showed that deregulated genes are mostly involved in the extracellular matrix and cytoskeleton. Furthermore, the p.T120A missense mutation in POC1A caused the formation of abnormal mitotic spindle structure, including supernumerary centrosomes, and changes in POC1A were accompanied by alterations in another centrosome-associated WD repeat protein p80-katanin. As a result, we identified a novel mutation in POC1A of patients with PD and showed that this mutation causes the formation of multiple numbers of centrioles and multipolar spindles with abnormal chromosome arrangement.
Asunto(s)
Centriolos/metabolismo , Enanismo/genética , Mutación Missense , Proteínas/genética , Análisis de Secuencia de ADN/métodos , Proteínas de Ciclo Celular , Células Cultivadas , Niño , Aberraciones Cromosómicas , Proteínas del Citoesqueleto , Exoma , Femenino , Fibroblastos/citología , Humanos , Masculino , Forboles , Piel/citologíaRESUMEN
BACKGROUND: Prostate cancer (PCa) is the most commonly diagnosed neoplasm and the second leading cause of cancer-related death among men in developed countries. There is no clear evidence showing the success of current screening tests in reducing mortality of PCa. In this study, we aimed to profile expressions of nine ABC transporters, ABCA5, ABCB1, ABCB6, ABCC1, ABCC2, ABCC3, ABCC5, ABCC10, and ABCF2, in recurrent, non-recurrent PCa and normal prostate tissues. METHODS: A total of 77 (39 recurrent, 38 non-recurrent) radical prostatectomy and 20 normal prostate samples, obtained from Baylor College of Medicine Prostate Cancer program, were included into the study and divided into two independent groups as test and validation sample sets. Differential expression of selected ABC transporters was assessed using quantitative real-time PCR (qRT-PCR). Pearson's correlation test, receiver operating characteristics (ROC) analysis and Kaplan-Meier test were used for statistical analysis. RESULTS: QRT-PCR results demonstrated the elevated expression of ABCA5, ABCB1, ABCB6, ABCC1, and ABCC2 as well as reduced expression of ABCC3 in PCa samples compared to normal prostate tissues. In addition, we found deregulation of ABCB1, ABCB6, ABCC3, and ABCC10 in recurrent PCa samples and validated differential expression of ABCB6, ABCC3, and ABCC10 in recurrent PCa compared to non-recurrent PCa. Pearson's correlation, ROC and Kaplan-Meier analysis revealed the power of these three ABC transporters for estimating prognosis of PCa. CONCLUSIONS: We demonstrated differential expression of ABC transporters both in tumor versus normal and recurrent versus non-recurrent comparisons. Our data suggest ABCB6, ABCC3, and ABCC10 as valuable predictors of PCa progression.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Recurrencia Local de Neoplasia/genética , Neoplasias de la Próstata/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Progresión de la Enfermedad , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Pronóstico , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patologíaRESUMEN
Prostate cancer (PCa) is one of the leading causes of cancer deaths in men. Since there are limited treatment options available for the advanced tumors, there is an urgent need for novel diagnostic tools for PCa. Prostate secretion samples (PSS) from 23 PCa and 25 benign prostate hyperplasia (BPH) patients were obtained from Urology Department of Bagcilar Educational and Research Hospital (Istanbul). MicroRNA (miRNA) profiling of eight PSS (four from BPH, four from PCa patients) was performed using microarray. Four of significantly deregulated miRNAs were further confirmed using quantitative reverse-transcription PCR (qRT-PCR). Statistical analysis was performed using Student's t-test. ROC curves were plotted with SPSS-15.0. In this study, we aimed to identify a miRNA expression signature that could be used to distinguish PCa from BPH. MiRNA profiling of four PCa and four BPH patients with microarray revealed that miR-361-3p, miR-133b and miR-221 were significantly downregulated and miR-203 was upregulated in PSS of PCa patients. Further qRT-PCR analysis confirmed the altered expressions of these four miRNAs in PSS of 23 PCa and 25 BPH patients. Four miRNAs, together and individually have much power (AUC; 0.950) than PSA has (AUC; 0.463) to discriminate PCa from BPH patients. We have shown for the first time in the literature the presence of miRNAs in the PSS. We suggest PSS as a powerful non-invasive source for evaluation of prognosis in PCa, since prostate massages can be easily applied during routine examination. Our results showed that certain differentially expressed miRNAs in PSS could be used as diagnostics markers.
Asunto(s)
Biomarcadores de Tumor/metabolismo , MicroARNs/metabolismo , Próstata/metabolismo , Neoplasias de la Próstata/metabolismo , Anciano , Área Bajo la Curva , Diagnóstico Diferencial , Progresión de la Enfermedad , Regulación hacia Abajo , Humanos , Masculino , Persona de Mediana Edad , Antígeno Prostático Específico/metabolismo , Hiperplasia Prostática/diagnóstico , Hiperplasia Prostática/metabolismo , Neoplasias de la Próstata/diagnóstico , Curva ROCRESUMEN
BACKGROUND: Prostate cancer (PCa) is the second most common tumor type related to mortality in males in the developed countries. Studies have demonstrated that therapeutic tools mostly ineffective to give positive outcome especially for PCa. Cancer stem cells are composed of a small cell population, which are supposed to have roles in tumorigenesis, metastasis, and tumor recurrence after chemo-radiotherapy. The aim of this research is to investigate expressions of stem cell markers in recurrent PCa and non-recurrent PCa tumors as well as in adjacent normal prostate tissues. METHODS: We compared the expression of important stemness regulators like SOX2, OCT4, KLF4, and ABCG2 in recurrent, non-recurrent PCa and adjacent normal tissue samples using quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: Our results demonstrated that SOX2 and OCT4 are strongly overexpressed in PCa samples. Recurrent PCa samples are markedly positive for stem cell markers SOX2, OCT4, and KLF4. Furthermore, non-recurrent PCa samples presented low levels of ABCG2, a multidrug resistance protein, compared to both normal and recurrent samples, which might be associated with chemo-sensitivity. CONCLUSIONS: Enhanced expression of ABCG2 and stem cell markers including SOX2, OCT4, and KLF4 in the recurrent PCa tissues postulates the suggestion that enrichment for cells with stem cell characteristics in these tissues might be playing a critical role for chemoresistance and recurrence of cancer.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/metabolismo , Biomarcadores de Tumor/metabolismo , Proteínas de Neoplasias/metabolismo , Recurrencia Local de Neoplasia/metabolismo , Células Madre Neoplásicas/metabolismo , Neoplasias de la Próstata/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Anciano , Regulación Neoplásica de la Expresión Génica , Humanos , Factor 4 Similar a Kruppel , Factores de Transcripción de Tipo Kruppel/metabolismo , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , Neoplasias de la Próstata/patología , Reacción en Cadena en Tiempo Real de la Polimerasa , Factores de Transcripción SOXB1/metabolismoRESUMEN
PURPOSE: A considerable percentage of patients with benign prostatic hyperplasia (BPH) also have additional cardiac pathologies, which often require anticoagulant therapy. The aim of this study was to evaluate the efficacy and safety of photoselective vaporization of the prostate (PVP) for BPH in cardiac patients receiving anticoagulant therapy. MATERIALS AND METHODS: A total of 67 patients suffering from BPH and high risk cardiac pathologies were operated on using laser prostatectomy. All patients had cardiac pathologies with bleeding disorders requiring anticoagulant use, and underwent standard urologic evaluation for BPH. Patients were treated with laser prostatectomy for relief of the obstruction using the KTP/532 laser energy at 80 W. RESULTS: The mean patient age was 71.4 years (range 55-80). Mean prostate volume on transrectal ultrasonography was 73.2 mL (range 44-120). Operation time ranged from 40 to 90 min, with an average value of 55 min. The average hospital stay was 48 hours (range 12-72) and the Foley catheters were removed within 48 hours, with a mean catheterization time of 34.2 +/- 5.9 hours (0-48). No patient required an additional procedure due to severe bleeding necessitating intervention during the early postoperative phase. Mean International symptoms scoring system (IPSS) values and post voiding residual volume decreased and peak urinary flow rate increased (p < 0.001). Our results showed that the mean prostate volume had decreased by 53% at 6 months. CONCLUSIONS: High-power photo selective laser vaporization prostatectomy is a feasible, safe, and effective alternative for the minimal invasive management of BPH, particularly in cardiac patients receiving anticoagulant therapy.
Asunto(s)
Anticoagulantes/administración & dosificación , Terapia por Láser/métodos , Complicaciones Posoperatorias/prevención & control , Hiperplasia Prostática/cirugía , Resección Transuretral de la Próstata/métodos , Obstrucción del Cuello de la Vejiga Urinaria/cirugía , Administración Oral , Anciano , Anciano de 80 o más Años , Estudios de Factibilidad , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Próstata/cirugía , Hiperplasia Prostática/complicaciones , Tromboembolia/prevención & control , Resección Transuretral de la Próstata/normas , Resultado del Tratamiento , Obstrucción del Cuello de la Vejiga Urinaria/etiologíaRESUMEN
OBJECTIVES: In this study, we aimed at investigating the expressions of miR-145 and its well-characterized direct targets on carboplatin treatment. STUDY DESIGN: Laboratory study. METHODS: The effect of carboplatin and miR-145 on the proliferative capacity of head and neck squamous cell carcinoma cells was evaluated using Cell Viability Detection Kit-8. Expressions of miR-145 and its targets were evaluated using quantitative real-time polymerase chain reaction on carboplatin treatment and p53 inhibition. Western blot was used to measure the levels of p53 and its acetylated versions in cells treated with carboplatin and/or pifithrin-α. RESULTS: We demonstrated that carboplatin induced the expression of miR-145 in a dose-dependent manner and suppressed the expressions of miR-145 direct targets. In addition, we showed that inhibition of p53 by pifithrin-α in carboplatin-treated cells reduced miR-145 expression and reversed the suppression of miR-145 direct targets. CONCLUSIONS: Considering all these findings together, one of the proposed mechanisms of carboplatin to kill cells might be the induction of miR-145 and deregulation of its targets in parallel, via p53 activation, which happens through carboplatin's DNA-damaging property. To the best of our knowledge, these findings are the first to reveal the relationship between carboplatin and miR-145 in cancer cells. LEVEL OF EVIDENCE: NA Laryngoscope, 2019.
Asunto(s)
Carboplatino/farmacología , Carcinoma de Células Escamosas/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , MicroARNs/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Benzotiazoles/farmacología , Western Blotting , Línea Celular Tumoral , Proliferación Celular , Humanos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tolueno/análogos & derivados , Tolueno/farmacología , TransfecciónRESUMEN
Multipotent precursors are plastic cells that generate different, stable fates at the correct number, place and time, to allow tissue and organ formation. While fate determinants are known to trigger specific transcriptional programs, the molecular pathway driving the progression from multipotent precursors towards stable and specific identities remains poorly understood. Here we demonstrate that, in Drosophila neural precursors, the glial determinant glial cell missing (Gcm) acts as a 'time bomb' and triggers its own degradation once the glial programme is stably activated. This requires a sequence of transcriptional and posttranscriptional loops, whereby a Gcm target first affects the expression and then acetylation of the fate determinant, thus controlling Gcm levels and stability over time. Defective homeostasis between the loops alters the neuron:glia ratio and freezes cells in an intermediate glial/neuronal phenotype. In sum, we identify an efficient strategy triggering cell identity, a process altered in pathological conditions such as cancer.
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Proteínas de Drosophila/metabolismo , Drosophila/metabolismo , Sistema Nervioso/citología , Sistema Nervioso/metabolismo , Animales , Linaje de la Célula , Drosophila/citología , Proteínas de Drosophila/genética , Regulación del Desarrollo de la Expresión Génica , Neuroglía/citología , Neuroglía/metabolismo , Neuronas/citología , Neuronas/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
INTRODUCTION: We tried to prove the effectiveness of trimetazidine (TMZ) on testicular torsion-detorsion injury. MATERIALS AND METHODS: 15 male rats were equally divided into three groups: group 1 was the sham-operated control group; group 2 had 2 h of unilateral testicular ischemia followed by 3 days of reperfusion, and group 3 had 2 h of unilateral testicular ischemia followed by 3 days of oral TMZ treatment (5 mg/kg, bid) during reperfusion. In the removed testicles, tissue reduced glutathione (GSH), glutathione reductase (GR), glutathione peroxidase (GPx), malondialdehyde (MDA) levels and pathological modified Johnson scores (MJS) were evaluated. Mann-Whitney U test was used for statistical evaluations. RESULTS: In group 2, on the ipsilateral side, GSH were significantly lower and MDA were higher than in groups 1 and 3, though GSH and MDA were not statistically different between groups 1 and 3. On the other hand, GPx in the control testicles of group 3 was significantly lower compared to those in the counterparts of both groups 1 and 2. Among three groups, GR determined in both testicles were not statistically different. On the ipsilateral side, MJS in group 3 were lower than in the sham group, but significantly higher than in group 2. CONCLUSIONS: According to this study, TMZ has an antioxidant effect on testicular torsion-detorsion injury, though the protective effect of TMZ seems to decrease in control testicles. Consequently it has been considered that TMZ can be only used in torsion patients with a healthy contralateral testicle after further studies have been conducted.
Asunto(s)
Daño por Reperfusión/tratamiento farmacológico , Testículo/efectos de los fármacos , Trimetazidina/farmacología , Vasodilatadores/farmacología , Animales , Masculino , Ratas , Ratas Sprague-Dawley , Testículo/patología , Resultado del TratamientoRESUMEN
PURPOSE: A considerable percentage of patients with benign prostatic hyperplasia (BPH) also have additional cardiac pathologies, which often require anticoagulant therapy. The aim of this study was to evaluate the efficacy and safety of photoselective vaporization of the prostate (PVP) for BPH in cardiac patients receiving anticoagulant therapy. MATERIALS AND METHODS: A total of 67 patients suffering from BPH and high risk cardiac pathologies were operated on using laser prostatectomy. All patients had cardiac pathologies with bleeding disorders requiring anticoagulant use, and underwent standard urologic evaluation for BPH. Patients were treated with laser prostatectomy for relief of the obstruction using the KTP/532 laser energy at 80 W. RESULTS: The mean patient age was 71.4 years (range 55-80). Mean prostate volume on transrectal ultrasonography was 73.2 mL (range 44-120). Operation time ranged from 40 to 90 min, with an average value of 55 min. The average hospital stay was 48 hours (range 12-72) and the Foley catheters were removed within 48 hours, with a mean catheterization time of 34.2 ± 5.9 hours (0-48). No patient required an additional procedure due to severe bleeding necessitating intervention during the early postoperative phase. Mean International symptoms scoring system (IPSS) values and post voiding residual volume decreased and peak urinary flow rate increased (p < 0.001). Our results showed that the mean prostate volume had decreased by 53 percent at 6 months. CONCLUSIONS: High-power photo selective laser vaporization prostatectomy is a feasible, safe, and effective alternative for the minimal invasive management of BPH, particularly in cardiac patients receiving anticoagulant therapy.