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1.
Metabolites ; 12(11)2022 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-36422258

RESUMEN

Oxidative stress may play an important role in colorectal cancer (CRC). The present study included 94 adult patients with CRC (52 men and 42 women) and 26 hospitalized patients (12 men and 14 women) in whom CRC was excluded (control group). During hospitalization, blood serum samples were collected from both groups. Apart from that, anthropometric measurements were taken and other clinical data were analyzed. Serum malondialdehyde (MDA) level, total oxidant status (TOS), total antioxidant status (TAS) and oxidative stress index (OSI) were assayed. Subsequently, the relationship between the analyzed oxidative stress markers and selected clinical characteristics was investigated in both groups. The evaluation of oxidative stress marker values demonstrated that MDA and TAS levels were significantly higher in the control group than the CRC group (p < 0.001 and p = 0.019, respectively), while TOS levels were significantly higher in the CRC group than the control group (p = 0.005). Significantly lower OSI levels were found in the control group than in the CRC group (p < 0.001). Similar results can be observed when performing ROC analysis (receiver operating characteristic curve). Preliminary statistical analysis demonstrated that MDA levels in the study group depend on the location of the primary tumour (p = 0.035). Based on the post hoc Tukey test, a relationship was demonstrated between the MDA level and the left and right side of the colon (p = 0.040). The results may be evidence for a higher level of oxidative stress, including a compromised antioxidative defence system, in patients with CRC.

2.
Curr Issues Mol Biol ; 44(10): 4517-4527, 2022 Sep 29.
Artículo en Inglés | MEDLINE | ID: mdl-36286024

RESUMEN

ADAM10 and ADAM17 have a role in inflammation and diseases associated with inflammation, such as diabetes, cardiovascular diseases (CVD) or cancer, e.g., colorectal cancer (CRC). The aim of this study was to evaluate whether ADAM10 and ADAM17 could be biomarkers of CRC. To achieve this goal, CRC tumors and a surgical margin from 72 patients with CRC were collected. The concentration of ADAM proteins was measured by the ELISA method. Results were analyzed statistically and compared with selected clinical parameters. We found that ADAM17 protein concentration in the tumor samples was higher in patients with diabetes mellitus type 2 (DMT2) (0.28 vs. 0.2 ng/µg protein; p = 0.01) and in the surgical margin was higher both in patients with coexisting DMT2 (0.22 vs. 0.16 ng/µg protein; p < 0.05) and CVD (0.21 vs. 0.13 ng/µg protein; p < 0.01). The concentration of ADAM10 was higher in the surgical margin than in the tumor (249.34 vs. 228.82 pg/µg protein), and the concentration of ADAM17 was higher in the tumor than in the margin (0.23 vs. 0.18 ng/µg protein), but results were not statistically significant. In conclusion, the results of our study indicate that ADAM10 and ADAM17 may be potential biomarkers in cancer linked with DMT2 and CVD as diseases associated with inflammation.

3.
Curr Med Sci ; 41(3): 522-528, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-34169422

RESUMEN

Colorectal cancer (CRC) is the third most frequently diagnosed cancer worldwide, responsible for over 880 000 deaths each year. Growth/differentiation factor 15 (GDF-15) is reported to be a promising diagnostic and prognostic factor in CRC. It induces pleiotropic effects in tumor cells: proliferation, stemness, invasion and metastasis. Some studies indicate that GDF-15 may stimulate angiogenesis in malignant neoplasms. However, it has not been investigated in CRC yet. The aim of our study was to determine the level of GDF-15 and the concentrations of hypoxia-inducible factor-1α (HIF-1α), VEGF-A and chemokine-like receptor 1 (CMKLR1) in tumor and margin specimens of CRC in relation to histological grade and TNM staging. The study comprised 33 samples of tumor and margin tissues obtained from CRC patients. To assess the concentration of GDF-15, HIF-1α, VEGF-A and CMKLR1, commercially available enzyme-linked immunosorbent assay (ELISA) kits were used. We found significantly increased levels of GDF-15 and CMKLR1 in tumor tissue compared to margin tissue and higher concentrations of HIF-1α and VEGF-A in margin tissue than in tumor tissue. The levels of GDF-15 and HIF-1α were significantly correlated with VEGF-A and CMKLR1 in margin tissue. In CRC, the increased level of GDF-15 might stimulate angiogenesis through upregulation of HIF-1α, VEGF A and CMKLR1 expression. Our study is the first one to reveal the correlation between the levels of GDF-15 and CMKLR1 in CRC. The elevated levels of HIF-1α and VEGF-A in tumor-free margin tissues suggest that noncancer cells in the tumor microenvironment are an important source of proangiogenic factors.


Asunto(s)
Neoplasias Colorrectales/genética , Factor 15 de Diferenciación de Crecimiento/genética , Receptores de Quimiocina/genética , Factor A de Crecimiento Endotelial Vascular/genética , Anciano , Línea Celular Tumoral , Proliferación Celular/genética , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/patología , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Masculino , Persona de Mediana Edad , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Metástasis de la Neoplasia , Estadificación de Neoplasias , Células Madre Neoplásicas/patología , Neovascularización Patológica/genética , Neovascularización Patológica/patología , Microambiente Tumoral/genética
4.
Dis Markers ; 2020: 6145604, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33133303

RESUMEN

Mounting evidence suggests that inflammation, immune response, and coagulation status determine many processes during the carcinogenesis pathway in colorectal cancer (CRC). Inflammation strongly promotes tumor formation, progression, and metastasis. The systemic inflammatory response (SIR) may be reflected by simple indicators evaluated on the basis of peripheral blood morphology parameters. The indices are easily obtained by the peripheral blood test and could be promising biomarkers for CRC. We present the results of the retrospective study evaluating the potential relation between the platelet indices (platelet count (PC), platelet-to-lymphocyte ratio (PLR), neutrophil platelet score (NPS), mean platelet volume (MPV), and MPV/PC ratio) and the clinicopathological features of CRC patients. The study included 247 patients (104 males and 143 females) aged 39-87 years with CRC stages II-IV. The complete blood counts with the automated differential counts were performed prior to the qualification to systemic treatment. High PC, high PLR, and NPS 0 were associated with older age and higher BMI of the patients. No link between the analyzed platelet indices and histological grade of the tumor, primary tumor location, and gender was noted. The patients aged ≥65 years were characterized by the higher MPV/PC ratio than the younger population. We observed a trend to the higher MPV/PC ratio among the patients with excessive body weight defined by BMI compared to BMI within normal limits. A higher frequency of PC > 400, NPS 1 and 2, and a trend to more frequent PLR ≥ 150 were observed in the subgroup with metastatic disease compared to individuals with CRC stages II and III. The presented results expand the knowledge on potential association between SIR parameters and other clinicopathological factors that should be considered during interpreting the prognostic and predictive value of the inflammation parameters.


Asunto(s)
Plaquetas , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/patología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Recuento de Linfocitos , Masculino , Volúmen Plaquetario Medio , Persona de Mediana Edad , Recuento de Plaquetas , Estudios Retrospectivos
5.
Exp Mol Pathol ; 113: 104377, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31926977

RESUMEN

INTRODUCTION: Colorectal cancer (CRC) is the second most common malignant neoplasm in men and third in women. It is also the third leading cause of cancer-related death, killing annually >700,000 patients in the world. The global burden of CRC is expected to increase by 60% to >2.2 million new cases and 1.1 million deaths by 2030. The pathogenesis of cancer mainly depends on angiogenesis. This process plays a key role in the growth and infiltration of tumors which is essential for distant metastases. A large number of biochemical pathways is involved in the regulation of angiogenesis. As a subject of our study, we chose chemerin/chemokine-like receptor 1 (CMKLR1) pathway which is responsible for the angiogenic processes in malignant neoplasms. AIM OF THE STUDY: To assess the CMKLR1 level and the concentrations of the two markers of angiogenesis, matrix metalloproteinase (MMP)-9 and vascular cell adhesion molecule (VCAM)-1, in tumor and margin tissues of CRC in relation to histological grade and TNM classification. MATERIALS AND METHODS: The study used 47 samples of tumor and margin tissues derived from CRC patients. To determine the concentration of CMKLR1, MMP-9, and VCAM-1, we used the commercially available enzyme-linked immunosorbent assay kit. RESULTS: We found a significantly higher concentration of CMKLR1 and MMP-9 in tumor tissue compared to margin. There was no difference in VCAM-1 concentration between tumor and margin. The margin concentration of CMKLR1 was significantly correlated with that of both MMP-9 and VCAM-1. The margin concentration of VCAM-1 was correlated with that of MMP-9. Additionally, we observed that the tumor levels of CMKLR1 and MMP-9 were positively correlated with the tumor size (T parameter). CONCLUSION: CMKLR1 activity may be associated with the angiogenic process in CRC via MMP-9 activity. Further research, involving a larger sample, may verify whether chemerin/CMKLR1 axis could be considered as a suitable target in novel molecular therapies.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias Colorrectales/irrigación sanguínea , Neoplasias Colorrectales/metabolismo , Neovascularización Patológica/metabolismo , Receptores de Quimiocina/metabolismo , Anciano , Neoplasias Colorrectales/patología , Femenino , Humanos , Masculino , Márgenes de Escisión , Metaloproteinasa 9 de la Matriz/metabolismo , Neovascularización Patológica/patología , Molécula 1 de Adhesión Celular Vascular/metabolismo
6.
Bioinformatics ; 36(4): 1121-1128, 2020 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-31584626

RESUMEN

MOTIVATION: Leucine-aspartic acid (LD) motifs are short linear interaction motifs (SLiMs) that link paxillin family proteins to factors controlling cell adhesion, motility and survival. The existence and importance of LD motifs beyond the paxillin family is poorly understood. RESULTS: To enable a proteome-wide assessment of LD motifs, we developed an active learning based framework (LD motif finder; LDMF) that iteratively integrates computational predictions with experimental validation. Our analysis of the human proteome revealed a dozen new proteins containing LD motifs. We found that LD motif signalling evolved in unicellular eukaryotes more than 800 Myr ago, with paxillin and vinculin as core constituents, and nuclear export signal as a likely source of de novo LD motifs. We show that LD motif proteins form a functionally homogenous group, all being involved in cell morphogenesis and adhesion. This functional focus is recapitulated in cells by GFP-fused LD motifs, suggesting that it is intrinsic to the LD motif sequence, possibly through their effect on binding partners. Our approach elucidated the origin and dynamic adaptations of an ancestral SLiM, and can serve as a guide for the identification of other SLiMs for which only few representatives are known. AVAILABILITY AND IMPLEMENTATION: LDMF is freely available online at www.cbrc.kaust.edu.sa/ldmf; Source code is available at https://github.com/tanviralambd/LD/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Asunto(s)
Proteoma , Secuencias de Aminoácidos , Ácido Aspártico , Humanos , Leucina , Prevalencia
7.
Dis Markers ; 2019: 5035234, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31565100

RESUMEN

Colorectal cancer is one of the most common cancers in the world. Due to its still undetermined pathogenesis, we are searching for signaling pathways that are important in the development of colorectal cancer. In this article, we present results of study on the role of ADAM proteins in colorectal cancer. The study included 85 adult colorectal cancer patients (48 men, 37 women) and 25 patients in the control group (after diagnostic colonoscopy-without cancer). During hospitalization, a serum sample (3 cm3) was collected from the study and control group, anthropometric measurements were conducted and others clinical data were analyzed. In the serum ADAM10, 12, 17, and 28, protein concentrations were determined and, in the next step, examined the relationship between ADAMs concentrations and selected clinical parameters in both groups. The analysis showed that serum levels of ADAM10 and ADAM28 are significantly higher in patients with colorectal cancer and correlate with histopathological grading and with presence of distant metastases. Moreover, noticed the trend to correlate concentrations of adamalysines with higher BMI score. One of the functions of adamalysines is the activation of growth factors involved in cancer, including IGF and TNFα. The increased activity of adamalysines in patients may play a role in the pathogenesis of colorectal cancer. Our study highlights the prevalence of metabolic disorders in the group of patients with diagnosed CRC, and this cancer seems to be a further complication of obesity.


Asunto(s)
Proteínas ADAM/sangre , Biomarcadores de Tumor/sangre , Neoplasias Colorrectales/sangre , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Colorrectales/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad
8.
Cent Eur J Immunol ; 43(1): 109-113, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29731694

RESUMEN

Colorectal cancer (CRC) is the third most common malignant neoplasm worldwide. In Poland, colorectal cancer ranks second in tumor incidence regardless of sex; moreover, there has been a steady increase in the incidence of CRC. CRC results from complex interactions between inherited susceptibility, clinical conditions and environmental/lifestyle-related risk factors such as physical inactivity, smoking, alcohol consumption, high-fat/low-fiber diet, and obesity/overweight. The activation of pathways associated with insulin resistance and insulin-like growth factors (IGF) appears to be the epidemiological link between the metabolic syndrome and the development of CRC, which is of particular importance. What is significantly associated with the pathway of IGF is ADAM12 and 28-protein, which belong to a broad family of the adamalysines. These proteins, by adjusting the bioavailability of growth factors, influence the process of carcinogenesis. The aim of this article is to analyze the role of selected adamalysines and activation of the IGF system associated with the formation of colon cancer.

9.
Sci Rep ; 8(1): 4977, 2018 03 21.
Artículo en Inglés | MEDLINE | ID: mdl-29563556

RESUMEN

MicroScale Thermophoresis (MST) is a frequently used method for the quantitative characterization of intermolecular interactions with several advantages over other technologies. One of these is its capability to determine equilibrium constants in solution including complex biological matrices such as cell lysates. MST requires one binding partner to be fluorescent, which is typically achieved by labeling target proteins with a suitable fluorophore. Here, we present a near-native, site-specific in situ labeling strategy for MST experiments that enables reliable measurements in cell lysates and that has distinct advantages over routine covalent labeling techniques. To this end, we exploited the high-affinity interaction of tris-NTA with oligohistidine-tags, which are popular for purification, immobilization or detection of recombinant proteins. We used various DYE-tris-NTA conjugates to successfully label His-tagged proteins that were either purified or a component of cell lysate. The RED-tris-NTA was identified as the optimal dye conjugate with a high affinity towards oligohistidine-tags, a high fluorescence signal and an optimal signal-to-noise ratio in MST binding experiments. Owing to its emission in the red region of the spectrum, it also enables reliable measurements in complex biological matrices such as cell lysates allowing a more physiologically realistic assessment and eliminating the need for protein purification.


Asunto(s)
Colorantes Fluorescentes/química , Coloración y Etiquetado/métodos , Difusión Térmica , Cromatografía de Afinidad , Histidina/química , Oligopéptidos/química , Unión Proteica , Conformación Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Espectrometría de Fluorescencia
10.
Int J Immunopathol Pharmacol ; 30(3): 322-326, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28627973

RESUMEN

Toll-like receptors (TLRs) are involved in transduction of molecular signals in immune process such as induction and regulation of immunity, production of cytokines, and recognition of specific molecular patterns on the surface of microorganisms, but also in cancer development-which was partially proven in previous studies. There is a lack of detailed research on differentiating levels of TLR expression in colorectal cancer at different stages of its advancement, so in our study we want to determine whether there is such a difference of TLRs and TLR-connected protein expression. In this study, 83 samples of colorectal adenocarcinoma (varying clinical degrees) and 40 slices of healthy colon tissue have been analyzed. The delivered material was subjected to homogenization and extraction of total RNA. The isolated RNA was subsequently purified and valued quantitatively and qualitatively. Quantification was performed using a spectrophotometer GeneQuant II. The RNA concentration in the tested samples was determined spectrophotometrically. A qualitative assessment was performed by performing electrophoresis on a 1% agarose gel stained with ethidium bromide. The expression profile of the genes encoding the TLRs was determined using oligonucleotide microarray HG-U133A. To determine the mRNA (messenger RNA), differentiate cancerous tissue from normal colon using PL-Grid Infrastructure. The results were analyzed statistically, taking a significance level P < 0.05. In the study were found three proteins, DUSP2, IFNγ, EIF4A1, associated with TLR system, that differentiate early stages of colorectal cancer of healthy tissue, moreover eleven, inter alia: vascular endothelial growth factor (VEGF), which differentiate high stage of cancer of healthy tissues. The results emphasize the role of pathways associated with TLR activation in the pathogenesis of colorectal cancer. In summary, molecular studies on the development of colorectal cancer will enable the introduction of minimally invasive genetic diagnosis of early forms of cancer. In addition, identification of new signaling pathways can provide the basis for developing new therapeutic methods.


Asunto(s)
Neoplasias Colorrectales/genética , Regulación Neoplásica de la Expresión Génica , Receptores Toll-Like/genética , Humanos , Análisis de Secuencia por Matrices de Oligonucleótidos , Transducción de Señal , Transcriptoma
11.
Postepy Hig Med Dosw (Online) ; 71(0): 315-327, 2017 May 05.
Artículo en Inglés | MEDLINE | ID: mdl-28513456

RESUMEN

Some molds commonly occurring in the natural environment produce mycotoxins in the process of secondary metabolism. Aspergillus flavus and A. parasiticus are species of molds, which are responsible for the production of aflatoxins and are crucial in the pathogenesis of human diseases. Aspergillus species present in decaying plants, the soil and their spores are transferred via air currents and insects to crops and food storages. Aflatoxins B1, B2, G1, G2, M1 and M2 are the most common derivatives of aflatoxins. Ingestion of contaminated food is the main source of exposure to aflatoxins, which adversely affect the health of both humans and animals. The compounds can cause acute or chronic toxic effects of a teratogenic, mutagenic, carcinogenic, immunotoxic or hepatotoxic character. Molecular aflatoxins affect DNA mutations, postranslation peptids chains modification, proteins and nucleic acids methylation and the formation of free radicals. Due to aflatoxins carcinogenic features and frequent occurrence in food and forages they are routinely examinated in some groceries and agricultural products.


Asunto(s)
Aflatoxinas/toxicidad , Aflatoxinas/efectos adversos , Animales , Aspergillus/química , Carcinógenos/toxicidad , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Humanos , Mutágenos/toxicidad , Teratógenos/toxicidad
12.
Int J Mol Sci ; 18(1)2017 Jan 06.
Artículo en Inglés | MEDLINE | ID: mdl-28067827

RESUMEN

Microsatellite instability (MSI) is a marker of the replication error phenotype. It is caused by impaired DNA mismatch repair processes (MMR), resulting in ineffectiveness of the mechanisms responsible for the DNA replication precision and postreplicative DNA repair. MSI underlies the pathogenesis of 10%-20% of colorectal cancer (CRC) cases. The data about the potential value of MMR status as a predictive factor for 5-fluorouracil (FU)-based chemotherapy remain unclear. According to National Comprehensive Cancer Network updated guidelines, MSI testing is recommended for all patients with stage II CRC because patients with MSI-H (high-frequency MSI) tumour may have a good prognosis and obtain no benefit from 5-FU-based adjuvant chemotherapy. The significance of the MSI status as a predictive factor for patients with metastatic disease was not confirmed. The association between the MSI status and the efficacy of the therapy based on anti-programmed death-1 receptor inhibitors requires further studies.


Asunto(s)
Colon/patología , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genética , Inestabilidad de Microsatélites , Recto/patología , Animales , Antimetabolitos Antineoplásicos/uso terapéutico , Colon/efectos de los fármacos , Colon/metabolismo , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Reparación de la Incompatibilidad de ADN , Fluorouracilo/uso terapéutico , Humanos , Pronóstico , Recto/efectos de los fármacos , Recto/metabolismo
13.
Postepy Hig Med Dosw (Online) ; 70(0): 872-80, 2016 Aug 17.
Artículo en Inglés | MEDLINE | ID: mdl-27594562

RESUMEN

Endothelins are a family of four endogenous peptides (ET-1, ET-2, ET-3, ET-4) secreted primarily in an inactive form by the endothelium. They are activated with the participation of converting enzyme. Numerous studies have described their pleiotropic biological activity. These peptides are involved, inter alia, in the regulation of processes such as cell proliferation, migration, angiogenesis and apoptosis. Their important role in the regulation of blood pressure, tissue perfusion (especially in the central nervous system), and myocardial systolic function is also known. Moreover, changes in transcriptional activity of endothelin and its receptors may be involved, with the participation of a number of signaling pathways, in carcinogenesis, and the pathogenesis of numerous diseases (heart, kidney, lung and skin disorders, especially with the component of fibrosis). Their role has been documented in the development of breast, prostatic, colorectal, ovarian, lung, kidney, and endometrial cancer, and in melanoma. In this article we present a brief description of the endothelin group and the participation of them and their receptors in carcinogenesis. We also try to show their role as prognostic and predictive factors in human malignant tumors. The article also refers to clinical trials on the use of preparations of endothelin receptor antagonists in the design of molecular therapeutic strategies in human malignancies.


Asunto(s)
Carcinogénesis/metabolismo , Antagonistas de los Receptores de Endotelina/uso terapéutico , Endotelinas , Neoplasias/metabolismo , Animales , Humanos , Neoplasias/diagnóstico , Neoplasias/tratamiento farmacológico , Neoplasias/patología
14.
Biomed Res Int ; 2016: 8208904, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27110571

RESUMEN

INTRODUCTION: The ability to form metastases which depends on the mechanisms of cell migration is an important element of the progression of cancer. In the present study we analyzed the genes involved in the regulation of migration in colon cancer cells. MATERIALS AND METHODS: A total of 20 pairs of surgically removed tumoral and healthy (marginal) tissues samples from colorectal cancer patients at clinical stages I-II and III-IV were analyzed. The isolation of RNA from CRC and normal tissues and its subsequent molecular analysis were performed according to manufacturer's instructions. Microarray data analysis was performed using the GeneSpring 11.5 platform and Significance Analysis of Microarrays (SAM). In SAM analysis to identify significantly differentially expressed genes score and q-value parameters were used. RESULTS: The largest increase in expression of genes was shown by MMP9, ADAM17, EphA2, and TIMP. CONCLUSIONS: Presented genes, especially ADAM17, MMP9, EphA2, TIMP1, ICAM 11, and CD4, may be used as prognostic markers of advanced stages of colorectal cancer, contributing to the development of new lines of therapy focused on reducing metastasis of the primary tumor.


Asunto(s)
Proteína ADAM17/biosíntesis , Biomarcadores de Tumor/biosíntesis , Movimiento Celular/genética , Neoplasias Colorrectales/genética , Proteína ADAM17/genética , Biomarcadores de Tumor/genética , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/cirugía , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Metaloproteinasa 9 de la Matriz/biosíntesis , Metaloproteinasa 9 de la Matriz/genética , Análisis por Micromatrices , Metástasis de la Neoplasia , Estadificación de Neoplasias , Receptor EphA2/biosíntesis , Receptor EphA2/genética , Inhibidores Tisulares de Metaloproteinasas/biosíntesis , Inhibidores Tisulares de Metaloproteinasas/genética
15.
Postepy Hig Med Dosw (Online) ; 70: 67-73, 2016 Feb 11.
Artículo en Polaco | MEDLINE | ID: mdl-26864065

RESUMEN

Increasing numbers of reports about the role of adamalysins (ADAM) in malignant tumors are being published. To date, more than 30 representatives of this group, out of which about 20 occur in humans, have been described. The ADAM family is a homogeneous group of proteins which regulate, from the stage of embryogenesis, a series of processes such as cell migration, adhesion, and cell fusion. Half of them have proteolytic activity and are involved in the degradation of the extracellular matrix and the disintegration of certain protein complexes, thereby regulating the bioavailability of various growth factors. Many of these functions have a direct role in the processes of carcinogenesis and promoting the growth of tumor, which affect some signaling pathways, including those related to insulin-like growth factors (IGF1, IGF2), vascular growth factor (VEGF), tumor necrosis factor α (TNFα) and the EGFR/HER pathway. Another branch of studies is the evaluation of the possibility of using members of ADAM family proteins in the diagnosis, especially in breast, colon and non- small cell lung cancer. The detection of concentrations of adamalysin in serum, urine and pleural aspirates might contribute to the development of methods of early diagnosis of cancer and monitoring the therapy. However, both the role of adamalysins in the development and progression of tumors and their importance as a diagnostic and predictive further research still need to be checked on large groups of patients.


Asunto(s)
Proteínas ADAM/metabolismo , Carcinogénesis/metabolismo , Neoplasias/metabolismo , Humanos , Neoplasias/diagnóstico
16.
Elife ; 4: e06866, 2015 Jul 29.
Artículo en Inglés | MEDLINE | ID: mdl-26222500

RESUMEN

The canonical action of the p85α regulatory subunit of phosphatidylinositol 3-kinase (PI3K) is to associate with the p110α catalytic subunit to allow stimuli-dependent activation of the PI3K pathway. We elucidate a p110α-independent role of homodimerized p85α in the positive regulation of PTEN stability and activity. p110α-free p85α homodimerizes via two intermolecular interactions (SH3:proline-rich region and BH:BH) to selectively bind unphosphorylated activated PTEN. As a consequence, homodimeric but not monomeric p85α suppresses the PI3K pathway by protecting PTEN from E3 ligase WWP2-mediated proteasomal degradation. Further, the p85α homodimer enhances the lipid phosphatase activity and membrane association of PTEN. Strikingly, we identified cancer patient-derived oncogenic p85α mutations that target the homodimerization or PTEN interaction surface. Collectively, our data suggest the equilibrium of p85α monomer-dimers regulates the PI3K pathway and disrupting this equilibrium could lead to disease development.


Asunto(s)
Fosfatidilinositol 3-Quinasa Clase Ia/metabolismo , Regulación de la Expresión Génica , Fosfohidrolasa PTEN/metabolismo , Multimerización de Proteína , Transducción de Señal , Fosfatidilinositol 3-Quinasa Clase Ia/química , Fosfatidilinositol 3-Quinasa Clase Ia/genética , Humanos , Modelos Biológicos , Modelos Moleculares , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Unión Proteica
17.
Prog Biophys Mol Biol ; 119(1): 60-71, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26093249

RESUMEN

The focal adhesion kinase (FAK) and the related protein-tyrosine kinase 2-beta (Pyk2) are highly versatile multidomain scaffolds central to cell adhesion, migration, and survival. Due to their key role in cancer metastasis, understanding and inhibiting their functions are important for the development of targeted therapy. Because FAK and Pyk2 are involved in many different cellular functions, designing drugs with partial and function-specific inhibitory effects would be desirable. Here, we summarise recent progress in understanding the structural mechanism of how the tug-of-war between intramolecular and intermolecular interactions allows these protein 'nanomachines' to become activated in a site-specific manner.


Asunto(s)
Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Secuencia de Aminoácidos , Animales , Descubrimiento de Drogas , Activación Enzimática/efectos de los fármacos , Proteína-Tirosina Quinasas de Adhesión Focal/antagonistas & inhibidores , Proteína-Tirosina Quinasas de Adhesión Focal/química , Humanos , Ligandos , Unión Proteica , Estructura Terciaria de Proteína
18.
EMBO J ; 33(4): 356-70, 2014 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-24480479

RESUMEN

Focal adhesion kinase (FAK) controls adhesion-dependent cell motility, survival, and proliferation. FAK has kinase-dependent and kinase-independent functions, both of which play major roles in embryogenesis and tumor invasiveness. The precise mechanisms of FAK activation are not known. Using x-ray crystallography, small angle x-ray scattering, and biochemical and functional analyses, we show that the key step for activation of FAK's kinase-dependent functions--autophosphorylation of tyrosine-397--requires site-specific dimerization of FAK. The dimers form via the association of the N-terminal FERM domain of FAK and are stabilized by an interaction between FERM and the C-terminal FAT domain. FAT binds to a basic motif on FERM that regulates co-activation and nuclear localization. FAK dimerization requires local enrichment, which occurs specifically at focal adhesions. Paxillin plays a dual role, by recruiting FAK to focal adhesions and by reinforcing the FAT:FERM interaction. Our results provide a structural and mechanistic framework to explain how FAK combines multiple stimuli into a site-specific function. The dimer interfaces we describe are promising targets for blocking FAK activation.


Asunto(s)
Quinasa 1 de Adhesión Focal/química , Secuencias de Aminoácidos , Animales , Cristalografía por Rayos X , Dimerización , Activación Enzimática , Quinasa 1 de Adhesión Focal/fisiología , Adhesiones Focales , Células HEK293 , Humanos , Modelos Moleculares , Fosforilación , Fosfotirosina/fisiología , Conformación Proteica , Procesamiento Proteico-Postraduccional , Estructura Terciaria de Proteína , Ratas , Proteínas Recombinantes de Fusión/química , Dispersión de Radiación
19.
Proc Natl Acad Sci U S A ; 109(52): 21408-13, 2012 Dec 26.
Artículo en Inglés | MEDLINE | ID: mdl-23236139

RESUMEN

In principle, evolutionary outcomes could be largely predicted if all of the relevant physicochemical variants of a particular protein function under selection were known and integrated into an appropriate physiological model. We have tested this principle by generating a family of variants of the tetracycline resistance protein TetX2 and identified the physicochemical properties most correlated with organismal fitness. Surprisingly, small changes in the K(m(MCN)), less than twofold, were sufficient to produce highly successful adaptive mutants over clinically relevant drug concentrations. We then built a quantitative model directly relating the in vitro physicochemical properties of the mutant enzymes to the growth rates of bacteria carrying a single chromosomal copy of the tet(X2) variants over a wide range of minocycline (MCN) concentrations. Importantly, this model allows the prediction of enzymatic properties directly from cellular growth rates as well as the physicochemical-fitness landscape of TetX2. Using experimental evolution and deep sequencing to monitor the allelic frequencies of the seven most biochemically efficient TetX2 mutants in 10 independently evolving populations, we showed that the model correctly predicted the success of the two most beneficial variants tet(X2)(T280A) and tet(X2)(N371I). The structure of the most efficient variant, TetX2(T280A), in complex with MCN at 2.7 Å resolution suggests an indirect effect on enzyme kinetics. Taken together, these findings support an important role for readily accessible small steps in protein evolution that can, in turn, greatly increase the fitness of an organism during natural selection.


Asunto(s)
Adaptación Biológica/genética , Evolución Biológica , Farmacorresistencia Microbiana/genética , Proteínas de Escherichia coli/metabolismo , Escherichia coli/genética , Aptitud Genética , Adaptación Biológica/efectos de los fármacos , Cromosomas Bacterianos/metabolismo , Cristalografía por Rayos X , Código de Barras del ADN Taxonómico , Farmacorresistencia Microbiana/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Escherichia coli/crecimiento & desarrollo , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/genética , Frecuencia de los Genes/genética , Aptitud Genética/efectos de los fármacos , Cinética , Minociclina/farmacología , Modelos Biológicos , Modelos Moleculares , Mutación/genética , Operón/genética , Selección Genética/efectos de los fármacos
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