RESUMEN
BACKGROUND: Ankylosing spondylitis (AS) is a chronic inflammatory disease known for causing pain, stiffness, and reduced mobility in the axial skeleton. Adalimumab, a tumor necrosis factor (TNF) inhibitor, has emerged as a promising therapeutic option for AS. METHODS: This systematic review involved a comprehensive search of randomized controlled trials related to AS treatment, conducted in major databases such as MEDLINE, Google Scholar, and PubMed. The search terms encompassed ankylosing spondylitis, adalimumab, methotrexate, other non-biologic DMARDs, glucocorticoids, NSAIDs, and analgesics. A total of 14 randomized controlled trials with 4,500 participants were included in the review. RESULTS: The review's results revealed that adalimumab demonstrated notable superiority when compared to a placebo. It effectively reduced disease activity, improved physical function, and lowered inflammatory markers such as C-reactive protein and erythrocyte sedimentation rate. Adalimumab demonstrated a favorable safety profile, with adverse events comparable to those observed with placebo. CONCLUSION: Based on the results, adalimumab is deemed an effective treatment for AS, showcasing its potential as a first-line therapeutic option. Notably, no significant increase in adverse events was observed compared to placebo. However, the conclusion emphasizes the need for further studies with extended follow-up durations to ascertain the long-term efficacy and safety of adalimumab in AS management. This systematic review provides valuable insights supporting the use of adalimumab in the treatment of AS and underscores the importance of ongoing investigations into its long-term effects to optimize its clinical utilization in AS patients.
Asunto(s)
Adalimumab , Antirreumáticos , Espondilitis Anquilosante , Espondilitis Anquilosante/tratamiento farmacológico , Humanos , Adalimumab/uso terapéutico , Antirreumáticos/uso terapéutico , Resultado del Tratamiento , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
The protein-specific methyltransferase Set7/9 is known for its ability to add methyl groups to lysine residues on many targets, including as histones H1.4, H2A, H2B, H3, and non-histone proteins such as p53, NFκB, E2F1, pRb, Hif1α, ß-catenin, STAT3, and YY1 transcription factors. Set7/9 affects both the landscape of histone modifications and the functionality of the aforementioned TFs, and acts as an essential mediator of vital cellular functions, regulating tumor growth and the neoplastic transformation of normal cells. The number of studies demonstrating the determining role of Set7/9 in cancer is growing. Importantly, the effect of Set7/9 on tumor progression is ambivalent and cancer-type dependent. In this study we analyzed the potential participation of Set7/9 in the essential cellular processes in breast cancer cells and revealed that Set7/9 may be involved in DNA damage signaling and DNA repair processes. We further demonstrated that Set7/9 expression is downregulated in cancerous breast tissues and inversely correlated to PARP1 expression level. Using breast cancer cell lines of HER2-positive and triple negative subtypes we have shown that the attenuation of Set7/9 led to the stabilization of PARP1 on both mRNA and protein levels that in turn resulted in cisplatin resistance acquiring. Finally, we demonstrated that the combination of cisplatin with FDA approved PARP1 inhibitor niraparib (Zejula) has a synergistic effect with cisplatin and thereby allows to overcome cisplatin resistance of Set7/9 deficient breast cancer cells.
Asunto(s)
Neoplasias de la Mama , Cisplatino , Humanos , Femenino , Cisplatino/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Histonas/metabolismo , Células MCF-7 , Poli(ADP-Ribosa) Polimerasa-1/genética , Poli(ADP-Ribosa) Polimerasa-1/metabolismoRESUMEN
The most often diagnosed and fatal malignancy in women is breast cancer. The International Agency for Research on Cancer (IARC) estimates that there are 2.26 million new cases of cancer in 2020. Adoptive cell therapy using T cells with chimeric antigen receptor shows potential for the treatment of solid tumors, such as breast cancer. In this work the effectiveness of CAR-T cells against monolayer and three-dimensional bioprinted tumor-like structures made of modified MCF-7 breast cancer cells was assessed. The cytokine profile of supernatants after co-cultivation of MCF-7 tumor cell models with CAR-T cells was also measured to reveal the inflammatory background associated with this interaction.
RESUMEN
In recent years, adoptive cell therapy has gained a new perspective of application due to the development of technologies and the successful clinical use of CAR-T cells for the treatment of patients with malignant B-cell neoplasms. However, the efficacy of CAR-T therapy against solid tumor remains a major scientific and clinical challenge. In this work, we evaluated the cytotoxicity of 2nd generation CAR-T cells against modified solid tumors cell lines-lung adenocarcinoma cell line H522, prostate carcinoma PC-3M, breast carcinoma MDA-MB-231, and epidermoid carcinoma A431 cell lines transduced with lentiviruses encoding red fluorescent protein Katushka2S and the CD19 antigen. A correlation was demonstrated between an increase in the secretion of proinflammatory cytokines and a decrease in the confluence of tumor cells' monolayer. The proposed approach can potentially be applied to preliminarily assess CAR-T cell efficacy for the treatment of solid tumors and estimate the risks of developing cytokine release syndrome.
RESUMEN
Estimates of external absorbed dose in experimental animals exposed to sprayed neutron-activated 56Mn powder are necessary for comparison with internal absorbed doses estimated under the same exposure conditions, which is required for a correct interpretation of the observed biological effects. It has been established that the measured dose of external absorbed dose as a result of gamma irradiation range 1-15 mGy, which is order of magnitude less than the maximal dose of internal gamma and beta irradiation of the whole body of the same experimental animals irradiated under the same conditions: according to the available literature data, the maximal values ââof absorbed dose of internal gamma-beta irradiation of the whole body are in the range of 330 mGy-1200 mGy for mice and 100 mGy-150 mGy for rats. It is concluded that under the conditions of experiments with dispersed neutron-activated powder 56MnO2, internal gamma-beta irradiation of experimental animals is the main factor of radiation exposure compared to external gamma irradiation.
Asunto(s)
Partículas beta , Neutrones , Animales , Rayos gamma , Ratones , Polvos , Dosis de Radiación , RatasRESUMEN
Medulloblastoma is one of the most common pediatric central nervous system malignancies worldwide, and it is characterized by frequent leptomeningeal metastasizing. We report a rare case of primary leptomeningeal medulloblastoma of an 11-year-old Caucasian girl with a long-term disease history, non-specific clinical course, and challenges in the diagnosis verification. To date, 4 cases of pediatric primary leptomeningeal medulloblastoma are reported, and all of them are associated with unfavorable outcomes. The approaches of neuroimaging and diagnosis verification are analyzed in the article to provide opportunities for effective diagnosis of this disease in clinical practice. The reported clinical case of the primary leptomeningeal medulloblastoma is characterized by MR images with non-specific changes in the brain and spinal cord and by 18FDG-PET/CT images with diffuse heterogeneous hyperfixation of the radiopharmaceutical along the whole spinal cord. The immunohistochemistry and next-generation sequencing analyses of tumor samples were performed for comprehensive characterization of the reported clinical case.
RESUMEN
In this work, we performed a comparative study of the formation of PML bodies by full-length PML isoforms and their C-terminal domains in the presence and absence of endogenous PML. Based on the analysis of the distribution of intrinsic disorder predisposition in the amino acid sequences of PML isoforms, regions starting from the amino acid residue 395 (i.e., sequences encoded by exons 4-6) were assigned as the C-terminal domains of these proteins. We demonstrate that each of the full-sized nuclear isoforms of PML is capable of forming nuclear liquid-droplet compartments in the absence of other PML isoforms. These droplets possess dynamic characteristics of the exchange with the nucleoplasm close to those observed in the wild-type cells. Only the C-terminal domains of the PML-II and PML-V isoforms are able to be included in the composition of the endogenous PML bodies, while being partially distributed in the nucleoplasm. The bodies formed by the C-terminal domain of the PML-II isoform are dynamic liquid droplet compartments, regardless of the presence or absence of endogenous PML. The C-terminal domain of PML-V forms dynamic liquid droplet compartments in the knockout cells (PML-/-), but when the C-terminus of the PML-V isoform is inserted into the existing endogenous PML bodies, the molecules of this protein cease to exchange with the nucleoplasm. It was demonstrated that the K490R substitution, which disrupts the PML sumoylation, promotes diffuse distribution of the C-terminal domains of PML-II and PML-V isoforms in endogenous PML knockout HeLa cells, but not in the wild-type cells. These data indicate the ability of the C-terminal domains of the PML-II and PML-V isoforms to form dynamic liquid droplet-like compartments, regardless of the ordered N-terminal RBCC motifs of the PML. This indicates a significant role of the non-specific interactions between the mostly disordered C-terminal domains of PML isoforms for the initiation of liquid-liquid phase separation (LLPS) leading to the formation of PML bodies.
Asunto(s)
Sustitución de Aminoácidos , Cuerpos Nucleares de la Leucemia Promielocítica/metabolismo , Proteína de la Leucemia Promielocítica/química , Proteína de la Leucemia Promielocítica/metabolismo , Secuencia de Aminoácidos , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Técnicas de Inactivación de Genes , Células HeLa , Humanos , Proteína de la Leucemia Promielocítica/genética , Dominios Proteicos , Isoformas de Proteínas/química , Isoformas de Proteínas/metabolismo , SumoilaciónRESUMEN
Immunotherapy using chimeric antigen receptor (CAR) T cells is a promising option for cancer treatment. However, T cells and CAR-T cells frequently become dysfunctional in cancer, where numerous evasion mechanisms impair antitumor immunity. Cancer frequently exploits intrinsic T cell dysfunction mechanisms that evolved for the purpose of defending against autoimmunity. T cell exhaustion is the most studied type of T cell dysfunction. It is characterized by impaired proliferation and cytokine secretion and is often misdefined solely by the expression of the inhibitory receptors. Another type of dysfunction is T cell senescence, which occurs when T cells permanently arrest their cell cycle and proliferation while retaining cytotoxic capability. The first section of this review provides a broad overview of T cell dysfunctional states, including exhaustion and senescence; the second section is focused on the impact of T cell dysfunction on the CAR-T therapeutic potential. Finally, we discuss the recent efforts to mitigate CAR-T cell exhaustion, with an emphasis on epigenetic and transcriptional modulation.
RESUMEN
Autophagy is a highly conserved process of cellular self-digestion that involves the formation of autophagosomes for the delivery of intracellular components and dysfunctional organelles to lysosomes. This process is induced by different signals including starvation, mitochondrial dysfunction, and DNA damage. The molecular link between autophagy and DNA damage is not well understood yet. Importantly, tumor cells utilize the mechanism of autophagy to cope with genotoxic anti-cancer drug therapy. Another mechanism of drug resistance is provided to cancer cells via the execution of the EMT program. One of the critical transcription factors of EMT is Zeb1. Here we demonstrate that Zeb1 is involved in the regulation of autophagy in several breast cancer cell models. On the molecular level, Zeb1 likely facilitates autophagy through the regulation of autophagic genes, resulting in increased LC3-II levels, augmented staining with Lysotracker, and increased resistance to several genotoxic drugs. The attenuation of Zeb1 expression in TNBC cells led to the opposite effect. Consequently, we propose that Zeb1 augments the resistance of breast cancer cells to genotoxic drugs, at least partially, via autophagy. Collectively, we have uncovered a novel function of Zeb1 in the regulation of autophagy in breast cancer cells.
Asunto(s)
Autofagia , Neoplasias de la Mama/patología , Resistencia a Antineoplásicos , Mutágenos/toxicidad , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/metabolismo , Autofagia/efectos de los fármacos , Autofagia/genética , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/genética , Línea Celular Tumoral , Daño del ADN , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Transición Epitelial-Mesenquimal/efectos de los fármacos , Transición Epitelial-Mesenquimal/genética , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Proteínas Asociadas a Microtúbulos/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genética , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/genéticaRESUMEN
Set7/9 is a lysine-specific methyltransferase, which regulates the functioning of both the histone and non-histone substrates, thereby significantly affecting the global gene expression landscape. Using microarray expression profiling, we have identified several key master regulators of metabolic networks, including c-Myc, that were affected by Set7/9 status. Consistent with this observation, c-Myc transcriptional targets-genes encoding the glycolytic enzymes hexokinase (HK2), aldolase (ALDOB), and lactate dehydrogenase (LDHA)-were upregulated upon Set7/9 knockdown (Set7/9KD). Importantly, we showed the short hairpin RNA (shRNA)-mediated attenuation of Set7/9 augmented c-Myc, GLUT1, HK2, ALDOA, and LDHA expression in non-small cell lung cancer (NSCLC) cell lines, not only at the transcriptional but also at the protein level. In line with this observation, Set7/9KD significantly augmented the membrane mitochondrial potential (MMP), glycolysis, respiration, and the proliferation rate of NSCLC cells. Importantly, all these effects of Set7/9 on cell metabolism were p53-independent. Bioinformatic analysis has shown a synergistic impact of Set7/9 together with either GLUT1, HIF1A, HK2, or LDHA on the survival of lung cancer patients. Based on these evidence, we hypothesize that Set7/9 can be an important regulator of energy metabolism in NSCLC.
RESUMEN
INTRODUCTION: Fluoxetine is used in the treatment of patients with recurrent depressive disorder. Some of these patients do not achieve an adequate response to a treatment regimen containing fluoxetine, and many of these patients experience dose-dependent adverse drug reactions. The cytochrome P450 enzyme CYP2D6 is involved in the biotransformation of fluoxetine, the activity of which is quite dependent on the polymorphism of the gene encoding this enzyme. OBJECTIVE: The objective of the study was to investigate the influence of the 1846G>A polymorphism of the CYP2D6 gene on the concentration/dose indicator of fluoxetine in patients diagnosed with major depressive disorder and comorbid alcohol use disorder. METHODS: Our study included 101 patients with major depressive disorder and alcohol use disorder (average age: 41.3±14.5 y) who were treated with fluoxetine at an average dose of 26.1±8.7 mg/d. Treatment efficacy was assessed using validated psychometric scales, and the safety/tolerability of the therapy was assessed using the Udvalg for Kliniske Undersogelser Side-Effect Rating Scale. Genotyping was done using a real-time polymerase chain reaction. Therapeutic drug monitoring was performed using high-performance liquid chromatography-mass spectrometry. RESULTS: CYP2D6 genotyping by polymorphic marker 1846G>A (rs3892097) in the 101 patients found that there were 81 patients (80.2%) with the GG genotype ("wild-type," normal metabolism), 20 (19.8%) with the GA genotype (intermediate metabolism), and no subjects with the AA genotype (poor metabolism). Statistically significant results in treatment efficacy as evaluated by Hamilton Rating Scale for Depression scores at the end of the treatment course were found: GG 9.0 [confidence interval (CI): 6.0; 12.0] and GA 12.0 (CI: 9.5; 14.0), P=0.005. Statistically significant results were also obtained for the safety profile as measured by scores on the Udvalg for Kliniske Undersogelser Side-Effect Rating Scale: GG 3.0 (CI 2.0; 4.0) and GA 5.0 (CI: 4.0; 5.0), P<0.001. Finally, a statistically significant difference was found in concentration/dose indicators of fluoxetine in patients with the different genotypes: GG 4.831 (CI: 3.654; 6.204) and GA 7.011 (CI: 5.431; 8.252), P<0.001. CONCLUSION: The effect of the genetic polymorphism of the CYP2D6 gene on the efficacy and safety profiles of fluoxetine was demonstrated in a group of 101 patients with major depressive disorder and alcohol use disorder.
Asunto(s)
Alcoholismo , Trastorno Depresivo Mayor , Adulto , Alcoholismo/tratamiento farmacológico , Alcoholismo/genética , Citocromo P-450 CYP2D6/genética , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/genética , Fluoxetina/efectos adversos , Humanos , Persona de Mediana Edad , Polimorfismo Genético , Resultado del TratamientoRESUMEN
The SET domain containing lysine-specific methyltransferase, Set7/9, covalently attaches methyl moieties to a variety of histone and non-histone substrates. Among the substrates of Set7/9 are: p53, NF-kB, PARP1, E2F1, and other transcription factors that regulate many vital processes in the cell. Through the post-translational regulation of these critical master-regulators Set7/9 is involved in regulation of cell proliferation, cancer progression, and DNA damage response. Noteworthy, the role of Set7/9 in tumorigenesis is contradictory and apparently depends on the cellular context. In this study, we investigated the effect of Set7/9 on tumorigenic characteristics of lung cancer cells. We showed that CRISPR/Cas9-mediated knock-out of Set7/9 in A549 and its shRNA-mediated knock-down in H1299 NSCLC cell lines both augment the proliferation rate of tumor cells compared to the matching wild-type cells. Mechanistically, ablation of Set7/9 increased the expression of cyclin A2 and D1 genes thereby promoting the accumulation of cells in S phase. Furthermore, knockout of Set7/9 decreased the expression of E-cadherin, whose product is critical for cell-cell interactions. Accordingly, this led to the increased migration of lung cancer cells. Finally, both ablation or pharmacological inhibition of Set7/9 enzymatic methyltransferase activity by the selective inhibitor (R)-PFI-2 sensitized NSCLC cells to genotoxic drug, doxorubicin. This effect was also recapitulated on patients-derived NSCLC cell lines. Taken together, our results suggest that Set7/9 plays anti-proliferative and DNA damage-protective roles in NSCLC cells and hence represents an attractive target for anti-cancer chemotherapy.
Asunto(s)
N-Metiltransferasa de Histona-Lisina/metabolismo , Antibióticos Antineoplásicos/farmacología , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Doxorrubicina/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , N-Metiltransferasa de Histona-Lisina/antagonistas & inhibidores , Humanos , Isoquinolinas/farmacología , Sulfonamidas/farmacología , Células Tumorales CultivadasRESUMEN
BACKGROUND: A promising approach to solve the problem of cytostatic toxicity is targeted drug transport using magnetic nanoparticles (MNPs). PURPOSE: To use calculation to determine the optimal characteristics of the magnetic field for controlling MNPs in the body, and to evaluate the efficiency of magnetically controlled delivery of MNPs in vitro and in vivo to a tumour site in mice. MATERIAL AND METHODS: For the in vitro study, reference MNPs were used, while for in vivo studies, MNPs coated in polylactide including fluorescent indocyanine (MNPs-ICG) were used. The in vivo luminescence intensity study was performed in mice with tumours, with and without of a magnetic field at the sites of interest. The studies were performed on a hydrodynamic stand developed at the Institute of Experimental Medicine of the Almazov National Medical Research Centre of the Ministry of Health of Russia. RESULTS: The use of neodymium magnets facilitated selective accumulation of MNPs. One minute after the administration of MNPs-ICG to mice with a tumour, MNPs-ICG predominantly accumulated in the liver, in the absence and presence of a magnetic field, which indicates its metabolic pathway. The intensity of the fluorescence in the animals' livers did not change over time, although an increase in fluorescence in the tumour was observed in the presence of a magnetic field. CONCLUSION: This type of MNP, used in combination with a magnetic field of calculated strength, can form the basis for the development of magnetically controlled transport of cytostatic drugs into tumour tissue.
Asunto(s)
Citostáticos , Nanopartículas de Magnetita , Animales , Campos Magnéticos , Nanopartículas Magnéticas de Óxido de Hierro , Magnetismo , RatonesRESUMEN
In this work, we put forward a hypothesis about the decisive role of multivalent nonspecific interactions in the early stages of PML body formation. Our analysis of the PML isoform sequences showed that some of the PML isoforms, primarily PML-II, are prone to phase separation due to their polyampholytic properties and the disordered structure of their C-terminal domains. The similarity of the charge properties of the C-terminal domains of PML-II and PML-VI isoforms made it possible for the first time to detect migration of PML-VI from PML bodies to the periphery of the cell nucleus, similar to the migration of PML-II isoforms. We found a population of "small" (area less than 1 µm2) spherical PML bodies with high dynamics of PML isoforms exchange with nucleoplasm and a low fraction of immobilized proteins, which indicates their liquid state properties. Such structures can act as "seeds" of functionally active PML bodies, providing the necessary concentration of PML isoforms for the formation of intermolecular disulfide bonds between PML monomers. FRAP analysis of larger bodies of toroidal topology showed the existence of an insoluble scaffold in their structure. The hypothesis about the role of nonspecific multiple weak interactions in the formation of PML bodies is further supported by the change in the composition of the scaffold proteins of PML bodies, but not their solidification, under conditions of induction of dimerization of PML isoforms under oxidative stress. Using the colocalization of ALT-associated PML bodies (APBs) with TRF1, we identified APBs and showed the difference in the dynamic properties of APBs and canonical PML bodies.
Asunto(s)
Cuerpos de Inclusión Intranucleares/metabolismo , Proteína de la Leucemia Promielocítica/metabolismo , Telómero/genética , Telómero/metabolismo , Secuencia de Aminoácidos , Biomarcadores , Núcleo Celular/metabolismo , Técnica del Anticuerpo Fluorescente , Humanos , Proteínas Intrínsecamente Desordenadas/metabolismo , Imagen Molecular , Estrés Oxidativo , Proteína de la Leucemia Promielocítica/química , Proteína de la Leucemia Promielocítica/genética , Unión Proteica , Isoformas de Proteínas , Transporte de Proteínas , Homeostasis del TelómeroRESUMEN
Autophagy is a special catabolic cellular program that is induced in response to deprivation of nutrients and energy starvation. During the execution of this program, cellular components, including aggregates, as well as damaged organelles and some proteins are encapsulated in special vesicles known as autophagosomes and subsequently are degraded after fusion of autophagosomes with lysosomes. Importantly, at late stages of tumorigenesis cancer cells employ autophagy to sustain proliferation in unfavorable conditions, including anti-cancer drug therapy. E3 ubiquitin ligases play an important role in controlling autophagy. Here we demonstrate that the E3 ligase, a p53-induced RING-H2 protein (Pirh2), is involved in the regulation of autophagy in non-small cell lung cancer cells. Knockdown of Pirh2 decreased the expression of genes involved in all steps of autophagy. Concomitantly, Pirh2 knockdown cell lines exhibited much less of the processed form of LC3 compared to the respective cell lines with normal levels of Pirh2. These results were confirmed by the immune fluorescence microscopy using LC3 antibody and the LysoTracker dye. In agreement with the protective role of autophagy, cells with attenuated expression of Pirh2 were more sensitive to the treatment with doxorubicin. Collectively, we have uncovered a novel function of Pirh2 in the regulation of autophagy in lung cancer cells.
Asunto(s)
Autofagia , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Neoplasias Pulmonares/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Proliferación Celular , Resistencia a Antineoplásicos , Humanos , Neoplasias Pulmonares/patología , Células Tumorales Cultivadas , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
PPM1D/Wip1 is a negative regulator of the tumor suppressor p53 and is overexpressed in several human solid tumors. Recent reports associate gain-of-function mutations of PPM1D in immune cells with worse outcomes for several human cancers. Here we show that mice with genetic knockout of Ppm1d or with conditional knockout of Ppm1d in the hematopoietic system, in myeloid cells, or in neutrophils all display significantly reduced growth of syngeneic melanoma or lung carcinoma tumors. Ppm1d knockout neutrophils infiltrate tumors extensively. Chemical inhibition of Wip1 in human or mouse neutrophils increases anti-tumor phenotypes, p53-dependent expression of co-stimulatory ligands, and proliferation of co-cultured cytotoxic T cells. These results suggest that inhibition of Wip1 in neutrophils enhances immune anti-tumor responses.
Asunto(s)
Daño del ADN , Inmunidad , Neutrófilos/metabolismo , Proteína Fosfatasa 2C/genética , Proteína Fosfatasa 2C/metabolismo , Animales , Antineoplásicos , Línea Celular Tumoral , Proliferación Celular , Femenino , Humanos , Pulmón , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fenotipo , Linfocitos T , Microambiente Tumoral , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
The RING-finger protein Pirh2 is a p53 family-specific E3 ubiquitin ligase. Pirh2 also ubiquitinates several other important cellular factors and is involved in carcinogenesis. However, its functional role in other cellular processes is poorly understood. To address this question, we performed a proteomic search for novel interacting partners of Pirh2. Using the GST-pulldown approach combined with LC-MS/MS, we revealed 225 proteins that interacted with Pirh2. We found that, according to the GO description, a large group of Pirh2-associated proteins belonged to the RNA metabolism group. Importantly, one of the identified proteins from that group was an RNA-binding protein ELAVL1 (HuR), which is involved in the regulation of splicing and protein stability of several oncogenic proteins. We demonstrated that Pirh2 ubiquitinated the HuR protein facilitating its proteasome-mediated degradation in cells. Importantly, the Pirh2-mediated degradation of HuR occurred in response to heat shock, thereby affecting the survival rate of HeLa cells under elevated temperature. Functionally, Pirh2-mediated degradation of HuR augmented the level of c-Myc expression, whose RNA level is otherwise attenuated by HuR. Taken together, our data indicate that HuR is a new target of Pirh2 and this functional interaction contributes to the heat-shock response of cancer cells affecting their survival.
Asunto(s)
Proteína 1 Similar a ELAV/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Línea Celular Tumoral , Proteína 1 Similar a ELAV/genética , Células HEK293 , Células HeLa , Humanos , Oncogenes , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
BACKGROUND: Myeloid sarcoma (MS) is a very rare condition, develops both in patients with other hematological neoplasms, and as isolated tumor. MS of the gynecologic tract is extremely rare. An available literature data about diagnosis and management of MS is summarized in the article. The role of chemotherapy, radiation therapy, surgery and bone marrow transplantation in the treatment is discussed. Polychemotherapy and allogeneic bone marrow transplantation were suggested to be the optimal treatment strategy of MS of the gynecological tract. The use of new targeted agents results in promising clinical data. CASE PRESENTATION: We are presenting a rare clinical case of a MS of the uterine cervix with concomitant bone marrow involvement and describe all the peculiarities of the clinical course, diagnosis, and treatment. The patient received chemotherapy followed by allogeneic bone marrow transplantation. The pre-transplant therapy allowed us to perform allogeneic bone marrow transplantation with the deepest response possible: complete PET-negative and MRD-negative remission of the disease. CONCLUSIONS: MS remains a subject of discussion regarding its diagnostic and therapeutic aspects. The use of novel targeting agents can be perspective option for patient with extramedullary disease.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Sarcoma Mieloide , Compuestos Bicíclicos Heterocíclicos con Puentes , Femenino , Humanos , Sarcoma Mieloide/tratamiento farmacológico , Trasplante de Células Madre , SulfonamidasRESUMEN
Cancer-testicular Antigens (CTAs) belong to a group of proteins that under normal conditions are strictly expressed in a male's reproductive tissues. However, upon malignisation, they are frequently re-expressed in neoplastic tissues of various origin. A number of studies have shown that different CTAs affect growth, migration and invasion of tumor cells and favor cancer development and metastasis. Two members of the CTA group, Semenogelin 1 and 2 (SEMG1 and SEMG2, or SEMGs) represent the major component of human seminal fluid. They regulate the motility and capacitation of sperm. They are often re-expressed in different malignancies including breast cancer. However, there is almost no information about the functional properties of SEMGs in cancer cells. In this review, we highlight the role of SEMGs in the reproductive system and also summarize the data on their expression and functions in malignant cells of various origins.
RESUMEN
The specific molecular features of cancer cells that distinguish them from the normal ones are denoted as "hallmarks of cancer". One of the critical hallmarks of cancer is an altered metabolism which provides tumor cells with energy and structural resources necessary for rapid proliferation. The key feature of a cancer-reprogrammed metabolism is its plasticity, allowing cancer cells to better adapt to various conditions and to oppose different therapies. Furthermore, the alterations of metabolic pathways in malignant cells are heterogeneous and are defined by several factors including the tissue of origin, driving mutations, and microenvironment. In the present review, we discuss the key features of metabolic reprogramming and plasticity associated with different stages of tumor, from primary tumors to metastases. We also provide evidence of the successful usage of metabolic drugs in anticancer therapy. Finally, we highlight new promising targets for the development of new metabolic drugs.