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1.
Cell Mol Life Sci ; 81(1): 276, 2024 Jun 23.
Artículo en Inglés | MEDLINE | ID: mdl-38909325

RESUMEN

N6-methyladenosine (m6A) is one of the most prevalent and conserved RNA modifications. It controls several biological processes, including the biogenesis and function of circular RNAs (circRNAs), which are a class of covalently closed-single stranded RNAs. Several studies have revealed that proteotoxic stress response induction could be a relevant anticancer therapy in Acute Myeloid Leukemia (AML). Furthermore, a strong molecular interaction between the m6A mRNA modification factors and the suppression of the proteotoxic stress response has emerged. Since the proteasome inhibition leading to the imbalance in protein homeostasis is strictly linked to the stress response induction, we investigated the role of Bortezomib (Btz) on m6A regulation and in particular its impact on the modulation of m6A-modified circRNAs expression. Here, we show that treating AML cells with Btz downregulated the expression of the m6A regulator WTAP at translational level, mainly because of increased oxidative stress. Indeed, Btz treatment promoted oxidative stress, with ROS generation and HMOX-1 activation and administration of the reducing agent N-acetylcysteine restored WTAP expression. Additionally, we identified m6A-modified circRNAs modulated by Btz treatment, including circHIPK3, which is implicated in protein folding and oxidative stress regulation. These results highlight the intricate molecular networks involved in oxidative and ER stress induction in AML cells following proteotoxic stress response, laying the groundwork for future therapeutic strategies targeting these pathways.


Asunto(s)
Adenosina , Leucemia Mieloide Aguda , Estrés Oxidativo , ARN Circular , Humanos , ARN Circular/genética , ARN Circular/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/tratamiento farmacológico , Adenosina/análogos & derivados , Adenosina/metabolismo , Adenosina/farmacología , Estrés Oxidativo/efectos de los fármacos , Bortezomib/farmacología , Línea Celular Tumoral , Especies Reactivas de Oxígeno/metabolismo , Factores de Empalme de ARN/metabolismo , Factores de Empalme de ARN/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Hemo-Oxigenasa 1/metabolismo , Hemo-Oxigenasa 1/genética , Proteínas Serina-Treonina Quinasas , Péptidos y Proteínas de Señalización Intracelular
2.
Cell Mol Life Sci ; 80(4): 111, 2023 Mar 31.
Artículo en Inglés | MEDLINE | ID: mdl-37002363

RESUMEN

Transmembrane semaphorins are signaling molecules, controlling axonal wiring and embryo development, which are increasingly implicated in human diseases. Semaphorin 6C (Sema6C) is a poorly understood family member and its functional role is still unclear. Upon targeting Sema6C expression in a range of cancer cells, we observed dramatic growth suppression, decreased ERK phosphorylation, upregulation of cell cycle inhibitor proteins p21, p27 and p53, and the onset of cell senescence, associated with activation of autophagy. These data are consistent with a fundamental requirement for Sema6C to support viability and growth in cancer cells. Mechanistically, we unveiled a novel signaling pathway elicited by Sema6C, and dependent on its intracellular domain, mediated by tyrosine kinases c-Abl and Focal Adhesion Kinase (FAK). Sema6C was found in complex with c-Abl, and induced its phosphorylation, which in turn led to FAK activation, independent of cell-matrix adhesion. Sema6C-induced FAK activity was furthermore responsible for increased nuclear localization of YAP transcriptional regulator. Moreover, Sema6C conferred YAP signaling-dependent long-term cancer cell survival upon nutrient deprivation. In conclusion, our findings demonstrate that Sema6C elicits a cancer promoting-signaling pathway sustaining cell viability and self-renewal, independent of growth factors and nutrients availability.


Asunto(s)
Neoplasias , Transducción de Señal , Humanos , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Supervivencia Celular , Quinasa 1 de Adhesión Focal/genética , Quinasa 1 de Adhesión Focal/metabolismo , Fosforilación , Proteínas de Ciclo Celular/metabolismo , Neoplasias/genética
3.
Cell Mol Life Sci ; 80(8): 202, 2023 Jul 13.
Artículo en Inglés | MEDLINE | ID: mdl-37442828

RESUMEN

The epidermal growth factor receptor (EGFR) is one of the main tumor drivers and is an important therapeutic target for many cancers. Calcium is important in EGFR signaling pathways. Sorcin is one of the most important calcium sensor proteins, overexpressed in many tumors, that promotes cell proliferation, migration, invasion, epithelial-to-mesenchymal transition, malignant progression and resistance to chemotherapeutic drugs. The present work elucidates a functional mechanism that links calcium homeostasis to EGFR signaling in cancer. Sorcin and EGFR expression are significantly correlated and associated with reduced overall survival in cancer patients. Mechanistically, Sorcin directly binds EGFR protein in a calcium-dependent fashion and regulates calcium (dys)homeostasis linked to EGF-dependent EGFR signaling. Moreover, Sorcin controls EGFR proteostasis and signaling and increases its phosphorylation, leading to increased EGF-dependent migration and invasion. Of note, silencing of Sorcin cooperates with EGFR inhibitors in the regulation of migration, highlighting calcium signaling pathway as an exploitable target to enhance the effectiveness of EGFR-targeting therapies.


Asunto(s)
Factor de Crecimiento Epidérmico , Neoplasias , Humanos , Factor de Crecimiento Epidérmico/farmacología , Factor de Crecimiento Epidérmico/metabolismo , Calcio , Transducción de Señal , Receptores ErbB/genética , Receptores ErbB/metabolismo , Línea Celular Tumoral , Movimiento Celular
4.
Drug Resist Updat ; 64: 100853, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35870226

RESUMEN

Protein biogenesis, maturation and degradation are tightly regulated processes that are governed by a complex network of signaling pathways. The endoplasmic reticulum (ER) is responsible for biosynthesis and maturation of secretory proteins. Circumstances that alter cellular protein homeostasis, determine accumulation of misfolded and unfolded proteins in the ER, a condition defined as ER stress. In case of stress, the ER activates an adaptive response called unfolded protein response (UPR), a series of pathways of major relevance for cancer biology. The UPR plays a preeminent role in adaptation of tumor cells to the harsh conditions that they experience, due to high rates of proliferation, metabolic abnormalities and hostile environment scarce in oxygen and nutrients. Furthermore, the UPR is among the main adaptive cell stress responses contributing to the development of resistance to drugs and chemotherapy. Clinical management of Acute Myeloid Leukemia (AML) has improved significantly in the last decade, thanks to development of molecular targeted therapies. However, the emergence of treatment-resistant clones renders the rate of AML cure dismal. Moreover, different cell populations that constitute the bone marrow niche recently emerged as a main determinant leading to drug resistance. Herein we summarize the most relevant literature regarding the role played by the UPR in expansion of AML and ability to develop drug resistance and we discuss different possible modalities to overturn this adaptive response against leukemia. To this aim, we also describe the interconnection of the UPR with other cellular stress responses regulating protein homeostasis. Finally, we review the newest findings about the crosstalk between AML cells and cells of the bone marrow niche, under physiological conditions and in response to therapies, discussing in particular the importance of the niche in supporting survival of AML cells by favoring protein homeostasis.


Asunto(s)
Leucemia Mieloide Aguda , Respuesta de Proteína Desplegada , Retículo Endoplásmico/metabolismo , Retículo Endoplásmico/patología , Homeostasis , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Oxígeno/metabolismo , Resultado del Tratamiento
5.
J Nanobiotechnology ; 19(1): 172, 2021 Jun 09.
Artículo en Inglés | MEDLINE | ID: mdl-34107976

RESUMEN

BACKGROUND: In recent years, the use of ferritins as nano-vehicles for drug delivery is taking center stage. Compared to other similar nanocarriers, Archaeoglobus fulgidus ferritin is particularly interesting due to its unique ability to assemble-disassemble under very mild conditions. Recently this ferritin was engineered to get a chimeric protein targeted to human CD71 receptor, typically overexpressed in cancer cells. RESULTS: Archaeoglobus fulgidus chimeric ferritin was used to generate a self-assembling hybrid nanoparticle hosting an aminic dendrimer together with a small nucleic acid. The positively charged dendrimer can indeed establish electrostatic interactions with the chimeric ferritin internal surface, allowing the formation of a protein-dendrimer binary system. The 4 large triangular openings on the ferritin shell represent a gate for negatively charged small RNAs, which access the internal cavity attracted by the dense positive charge of the dendrimer. This ternary protein-dendrimer-RNA system is efficiently uptaken by acute myeloid leukemia cells, typically difficult to transfect. As a proof of concept, we used a microRNA whose cellular delivery and induced phenotypic effects can be easily detected. In this article we have demonstrated that this hybrid nanoparticle successfully delivers a pre-miRNA to leukemia cells. Once delivered, the nucleic acid is released into the cytosol and processed to mature miRNA, thus eliciting phenotypic effects and morphological changes similar to the initial stages of granulocyte differentiation. CONCLUSION: The results here presented pave the way for the design of a new family of protein-based transfecting agents that can specifically target a wide range of diseased cells.


Asunto(s)
Dendrímeros/química , Sistemas de Liberación de Medicamentos/métodos , Ferritinas/química , Leucemia Mieloide/tratamiento farmacológico , Nanopartículas/química , Ácidos Nucleicos/química , Antígenos CD , Archaeoglobus fulgidus/genética , Archaeoglobus fulgidus/metabolismo , Línea Celular Tumoral , Ferritinas/genética , Humanos , MicroARNs/química , MicroARNs/farmacología , Receptores de Transferrina
6.
Mol Reprod Dev ; 87(4): 419-429, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32020743

RESUMEN

Glial cell line-derived neurotrophic factor (GDNF) and retinoic acid (RA) are two molecules crucial for the regulation of the spermatogonial compartment of the testis. During the cycle of the seminiferous epithelium, their relative concentration oscillates with lower GDNF levels in stages where RA levels are high. It has been recently shown that RA negatively regulates Gdnf expression but the mechanisms behind are so far unknown. Here, we show that RA directly downregulates Gdnf mRNA levels in primary murine Sertoli cells through binding of RARα to a novel DR5-RARE on Gdnf promoter. Pharmacological inhibition and chromatin immunoprecipitation-quantitative polymerase chain reaction analysis suggested that the underlying mechanism involved histone deacetylase activity and epigenetic repression of Gdnf promoter upon RA treatment.


Asunto(s)
Regulación hacia Abajo/genética , Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Células de Sertoli/metabolismo , Tretinoina/metabolismo , Tretinoina/farmacología , Animales , Benzoatos/farmacología , Células Cultivadas , Regulación hacia Abajo/efectos de los fármacos , Epigénesis Genética/efectos de los fármacos , Epigénesis Genética/genética , Factor Neurotrófico Derivado de la Línea Celular Glial/genética , Masculino , Ratones , Regiones Promotoras Genéticas , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptor alfa de Ácido Retinoico/genética , Receptor alfa de Ácido Retinoico/metabolismo , Epitelio Seminífero/metabolismo , Células de Sertoli/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Espermatogonias/metabolismo , Estilbenos/farmacología , Transfección
7.
Breast Cancer Res ; 20(1): 59, 2018 06 19.
Artículo en Inglés | MEDLINE | ID: mdl-29921315

RESUMEN

BACKGROUND: As crucial regulators of the immune response against pathogens, macrophages have been extensively shown also to be important players in several diseases, including cancer. Specifically, breast cancer macrophages tightly control the angiogenic switch and progression to malignancy. ID4, a member of the ID (inhibitors of differentiation) family of proteins, is associated with a stem-like phenotype and poor prognosis in basal-like breast cancer. Moreover, ID4 favours angiogenesis by enhancing the expression of pro-angiogenic cytokines interleukin-8, CXCL1 and vascular endothelial growth factor. In the present study, we investigated whether ID4 protein exerts its pro-angiogenic function while also modulating the activity of tumour-associated macrophages in breast cancer. METHODS: We performed IHC analysis of ID4 protein and macrophage marker CD68 in a triple-negative breast cancer series. Next, we used cell migration assays to evaluate the effect of ID4 expression modulation in breast cancer cells on the motility of co-cultured macrophages. The analysis of breast cancer gene expression data repositories allowed us to evaluate the ability of ID4 to predict survival in subsets of tumours showing high or low macrophage infiltration. By culturing macrophages in conditioned media obtained from breast cancer cells in which ID4 expression was modulated by overexpression or depletion, we identified changes in the expression of ID4-dependent angiogenesis-related transcripts and microRNAs (miRNAs, miRs) in macrophages by RT-qPCR. RESULTS: We determined that ID4 and macrophage marker CD68 protein expression were significantly associated in a series of triple-negative breast tumours. Interestingly, ID4 messenger RNA (mRNA) levels robustly predicted survival, specifically in the subset of tumours showing high macrophage infiltration. In vitro and in vivo migration assays demonstrated that expression of ID4 in breast cancer cells stimulates macrophage motility. At the molecular level, ID4 protein expression in breast cancer cells controls, through paracrine signalling, the activation of an angiogenic programme in macrophages. This programme includes both the increase of angiogenesis-related mRNAs and the decrease of members of the anti-angiogenic miR-15b/107 group. Intriguingly, these miRNAs control the expression of the cytokine granulin, whose enhanced expression in macrophages confers increased angiogenic potential. CONCLUSIONS: These results uncover a key role for ID4 in dictating the behaviour of tumour-associated macrophages in breast cancer.


Asunto(s)
Neoplasias de la Mama/genética , Proteínas Inhibidoras de la Diferenciación/genética , Neovascularización Patológica/genética , Neoplasias de la Mama Triple Negativas/genética , Antígenos CD/genética , Antígenos de Diferenciación Mielomonocítica/genética , Neoplasias de la Mama/patología , Línea Celular Tumoral , Reprogramación Celular/genética , Citocinas/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Interleucina-8/genética , Macrófagos/patología , MicroARNs/genética , Neovascularización Patológica/patología , Neoplasias de la Mama Triple Negativas/patología , Factor A de Crecimiento Endotelial Vascular/genética
8.
Mol Cancer ; 16(1): 88, 2017 05 10.
Artículo en Inglés | MEDLINE | ID: mdl-28486946

RESUMEN

BACKGROUND: Thymoma and thymic carcinoma are the most frequent subtypes of thymic epithelial tumors (TETs). A relevant advance in TET management could derive from a deeper molecular characterization of these neoplasms. We previously identified a set of microRNA (miRNAs) differentially expressed in TETs and normal thymic tissues and among the most significantly deregulated we described the down-regulation of miR-145-5p in TET. Here we describe the mRNAs diversely regulated in TETs and analyze the correlation between these and the miRNAs previously identified, focusing in particular on miR-145-5p. Then, we examine the functional role of miR-145-5p in TETs and its epigenetic transcriptional regulation. METHODS: mRNAs expression profiling of a cohort of fresh frozen TETs and normal tissues was performed by microarray analysis. MiR-145-5p role in TETs was evaluated in vitro, modulating its expression in a Thymic Carcinoma (TC1889) cell line. Epigenetic transcriptional regulation of miR-145-5p was examined by treating the TC1889 cell line with the HDAC inhibitor Valproic Acid (VPA). RESULTS: Starting from the identification of a 69-gene signature of miR-145-5p putative target mRNAs, whose expression was inversely correlated to that of miR-145-5p, we followed the expression of some of them in vitro upon overexpression of miR-145-5p; we observed that this resulted in the down-regulation of the target genes, impacting on TETs cancerous phenotype. We also found that VPA treatment of TC1889 cells led to miR-145-5p up-regulation and concomitant down-regulation of miR-145-5p target genes and exhibited antitumor effects, as indicated by the induction of cell cycle arrest and by the reduction of cell viability, colony forming ability and migration capability. The importance of miR-145-5p up-regulation mediated by VPA is evidenced by the fact that hampering miR-145-5p activity by a LNA inhibitor reduced the impact of VPA treatment on cell viability and colony forming ability of TET cells. Finally, we observed that VPA was also able to enhance the response of TET cells to cisplatin and erlotinib. CONCLUSIONS: Altogether our results suggest that the epigenetic regulation of miR-145-5p expression, as well as the modulation of its functional targets, could be relevant players in tumor progression and treatment response in TETs.


Asunto(s)
Epigénesis Genética , MicroARNs/genética , Neoplasias Glandulares y Epiteliales/genética , Timoma/genética , Neoplasias del Timo/genética , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Clorhidrato de Erlotinib/administración & dosificación , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Neoplasias Glandulares y Epiteliales/patología , ARN Mensajero/genética , Timoma/tratamiento farmacológico , Timoma/patología , Neoplasias del Timo/tratamiento farmacológico , Neoplasias del Timo/patología
9.
FASEB J ; 30(4): 1404-15, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26672000

RESUMEN

Understanding the regulation of the stem cell fate is fundamental for designing novel regenerative medicine strategies. Previous studies have suggested that pharmacological treatments with small molecules provide a robust and reversible regulation of the stem cell program. Previously, we showed that treatment with a vanadium compound influences muscle cell fatein vitro In this study, we demonstrate that treatment with the phosphotyrosine phosphatase inhibitor bisperoxovanadium (BpV) drives primary muscle cells to a poised stem cell stage, with enhanced function in muscle regenerationin vivofollowing transplantation into injured muscles. Importantly, BpV-treated cells displayed increased self-renewal potentialin vivoand replenished the niche in both satellite and interstitial cell compartments. Moreover, we found that BpV treatment induces specific activating chromatin modifications at the promoter regions of genes associated with stem cell fate, includingSca-1andPw1 Thus, our findings indicate that BpV resets the cell fate program by specific epigenetic regulations, such that the committed myogenic cell fate is redirected to an earlier progenitor cell fate stage, which leads to an enhanced regenerative stem cell potential.-Smeriglio, P., Alonso-Martin, S., Masciarelli, S., Madaro, L., Iosue, I., Marrocco, V., Relaix, F., Fazi, F., Marazzi, G., Sassoon, D. A., Bouché, M. Phosphotyrosine phosphatase inhibitor bisperoxovanadium endows myogenic cells with enhanced muscle stem cell functionsviaepigenetic modulation of Sca-1 and Pw1 promoters.


Asunto(s)
Antígenos Ly/genética , Epigénesis Genética , Factores de Transcripción de Tipo Kruppel/genética , Proteínas de la Membrana/genética , Células Musculares/efectos de los fármacos , Mioblastos Esqueléticos/efectos de los fármacos , Regiones Promotoras Genéticas/genética , Compuestos de Vanadio/farmacología , Animales , Western Blotting , Línea Celular , Células Cultivadas , Expresión Génica/efectos de los fármacos , Ratones Desnudos , Ratones Transgénicos , Microscopía Fluorescente , Células Musculares/citología , Células Musculares/metabolismo , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/lesiones , Músculo Esquelético/fisiopatología , Mioblastos Esqueléticos/citología , Mioblastos Esqueléticos/metabolismo , Proteínas Tirosina Fosfatasas/antagonistas & inhibidores , Proteínas Tirosina Fosfatasas/metabolismo , Regeneración/efectos de los fármacos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
10.
Cell Death Dis ; 15(2): 169, 2024 Feb 23.
Artículo en Inglés | MEDLINE | ID: mdl-38395995

RESUMEN

Phosphodiesterase 2A (Pde2A) is a dual-specific PDE that breaks down both cAMP and cGMP cyclic nucleotides. We recently highlighted a direct relationship between Pde2A impairment, a consequent increase of cAMP, and the appearance of mouse congenital heart defects (CHDs). Here we aimed to characterize the pathways involved in the development of CHDs and in their prevention by pharmacological approaches targeting cAMP and cGMP signaling. Transcriptome analysis revealed a modulation of more than 500 genes affecting biological processes involved in the immune system, cardiomyocyte development and contractility, angiogenesis, transcription, and oxidative stress in hearts from Pde2A-/- embryos. Metoprolol and H89 pharmacological administration prevented heart dilatation and hypertabeculation in Pde2A-/- embryos. Metoprolol was also able to partially impede heart septum defect and oxidative stress at tissue and molecular levels. Amelioration of cardiac defects was also observed by using the antioxidant NAC, indicating oxidative stress as one of the molecular mechanisms underpinning the CHDs. In addition, Sildenafil treatment recovered cardiac defects suggesting the requirement of cAMP/cGMP nucleotides balance for the correct heart development.


Asunto(s)
Fosfodiesterasas de Nucleótidos Cíclicos Tipo 2 , Cardiopatías Congénitas , Ratones , Animales , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 2/genética , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 2/metabolismo , Metoprolol , Transducción de Señal , GMP Cíclico/metabolismo , Cardiopatías Congénitas/genética , Cardiopatías Congénitas/prevención & control , Estrés Oxidativo
11.
J Exp Clin Cancer Res ; 42(1): 223, 2023 Aug 31.
Artículo en Inglés | MEDLINE | ID: mdl-37653435

RESUMEN

BACKGROUND: Acute myeloid leukemia (AML) patients bearing the ITD mutation in the tyrosine kinase receptor FLT3 (FLT3-ITD) present a poor prognosis and a high risk of relapse. FLT3-ITD is retained in the endoplasmic reticulum (ER) and generates intrinsic proteotoxic stress. We devised a strategy based on proteotoxic stress, generated by the combination of low doses of the differentiating agent retinoic acid (R), the proteasome inhibitor bortezomib (B), and the oxidative stress inducer arsenic trioxide (A). METHODS: We treated FLT3-ITD+ AML cells with low doses of the aforementioned drugs, used alone or in combinations and we investigated the induction of ER and oxidative stress. We then performed the same experiments in an in vitro co-culture system of FLT3-ITD+ AML cells and bone marrow stromal cells (BMSCs) to assess the protective role of the niche on AML blasts. Eventually, we tested the combination of drugs in an orthotopic murine model of human AML. RESULTS: The combination RBA exerts strong cytotoxic activity on FLT3-ITD+ AML cell lines and primary blasts isolated from patients, due to ER homeostasis imbalance and generation of oxidative stress. AML cells become completely resistant to the combination RBA when treated in co-culture with BMSCs. Nonetheless, we could overcome such protective effects by using high doses of ascorbic acid (Vitamin C) as an adjuvant. Importantly, the combination RBA plus ascorbic acid significantly prolongs the life span of a murine model of human FLT3-ITD+ AML without toxic effects. Furthermore, we show for the first time that the cross-talk between AML and BMSCs upon treatment involves disruption of the actin cytoskeleton and the actin cap, increased thickness of the nuclei, and relocalization of the transcriptional co-regulator YAP in the cytosol of the BMSCs. CONCLUSIONS: Our findings strengthen our previous work indicating induction of proteotoxic stress as a possible strategy in FLT3-ITD+ AML therapy and open to the possibility of identifying new therapeutic targets in the crosstalk between AML and BMSCs, involving mechanotransduction and YAP signaling.


Asunto(s)
Citoprotección , Tretinoina , Humanos , Animales , Ratones , Tretinoina/farmacología , Modelos Animales de Enfermedad , Mecanotransducción Celular , Estrés Proteotóxico , Ácido Ascórbico , Muerte Celular
12.
Noncoding RNA ; 8(4)2022 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-35893233

RESUMEN

Acute myeloid leukemia (AML) is a hematological malignancy originating from defective hematopoietic stem cells in the bone marrow. In spite of the recent approval of several molecular targeted therapies for AML treatment, disease recurrence remains an issue. Interestingly, increasing evidence has pointed out the relevance of bone marrow (BM) niche remodeling during leukemia onset and progression. Complex crosstalk between AML cells and microenvironment components shapes the leukemic BM niche, consequently affecting therapy responsiveness. Notably, circular RNAs are a new class of RNAs found to be relevant in AML progression and chemoresistance. In this review, we provided an overview of AML-driven niche remodeling. In particular, we analyzed the role of circRNAs and their possible contribution to cell-cell communication within the leukemic BM microenvironment. Understanding these mechanisms will help develop a more effective treatment for AML.

13.
Front Immunol ; 13: 867181, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35529877

RESUMEN

Thymic Epithelial Tumors (TETs) arise from epithelial cells of the thymus and are very rare neoplasms comprising Thymoma, Thymic carcinoma, and Thymic Neuroendocrine tumors that still require in-depth molecular characterization. Long non-coding RNAs (lncRNAs) are emerging as relevant gene expression modulators involved in the deregulation of several networks in almost all types of human cancer, including TETs. LncRNAs act at different control levels in the regulation of gene expression, from transcription to translation, and modulate several pathways relevant to cell fate determination under normal and pathological conditions. The activity of lncRNAs is strongly dependent on their expression, localization, and post-transcriptional modifications. Starting from our recently published studies, this review focuses on the involvement of lncRNAs in the acquisition of malignant traits by neoplastic thymic epithelial cells, and describes the possible use of these molecules as targets for the design of novel therapeutic approaches specific for TET. Furthermore, the involvement of lncRNAs in myasthenia gravis (MG)-related thymoma, which is still under investigation, is discussed.


Asunto(s)
Neoplasias Glandulares y Epiteliales , ARN Largo no Codificante , Timoma , Neoplasias del Timo , Células Epiteliales/metabolismo , Humanos , Neoplasias Glandulares y Epiteliales/genética , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Timoma/genética , Timoma/patología , Neoplasias del Timo/genética , Neoplasias del Timo/patología
14.
Clin Epigenetics ; 13(1): 173, 2021 09 16.
Artículo en Inglés | MEDLINE | ID: mdl-34530916

RESUMEN

BACKGROUND: Thymic epithelial tumors (TETs) are rare neoplasms, originating from epithelial thymic cells. The oncogenic potential of these rare neoplasms is still largely undefined, and a deeper molecular characterization could result in a relevant advance in their management, greatly improving diagnosis, prognosis and treatment choice. Deregulation of N6-methyladenosine (m6A) RNA modification, catalyzed by the METTL3/METTL14 methyltransferase complex, is emerging as a relevant event in cell differentiation and carcinogenesis. Various studies have reported that altered expression of METTL3 is associated with an aggressive malignant phenotype and favors migration and invasiveness, but its role in Thymic Tumors remains unknown. RESULTS: In this study, we characterized that METTL3 contributes to Thymic Epithelial Tumor phenotype. We evidenced that METTL3 is overexpressed in tumor tissue compared to normal counterpart. Silencing of METTL3 expression in thymic carcinoma cells results in reduced cell proliferation and overall translation rate. Of note, METTL3 is responsible for the induction of c-MYC expression in TET cells. Specifically, high expression of c-MYC protein is enabled by lncRNA MALAT1, which is methylated and delocalized by METTL3. Interestingly, blocking of c-MYC by using JQ1 inhibitor cooperates with METTL3 depletion in the inhibition of proliferation and induction of cell death. CONCLUSION: This study highlighted METTL3 as a tumor promoter in Thymic tumors and c-MYC as a promising target to be exploited for the treatment of TET.


Asunto(s)
Metilación de ADN/genética , Regulación Neoplásica de la Expresión Génica/genética , Metiltransferasas/genética , Neoplasias Glandulares y Epiteliales/genética , Proteínas Proto-Oncogénicas c-myc/genética , Neoplasias del Timo/genética , Factores de Transcripción/genética , Células Cultivadas , Humanos
15.
Cell Death Dis ; 12(10): 870, 2021 09 24.
Artículo en Inglés | MEDLINE | ID: mdl-34561421

RESUMEN

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm caused by the presence of tyrosine kinase BCR-ABL1 fusion protein, which deregulate transcription and mRNA translation. Tyrosine kinase inhibitors (TKIs) are the first-choice treatment. However, resistance to TKIs remains a challenge to cure CML patients. Here, we reveal that the m6A methyltransferase complex METTL3/METTL14 is upregulated in CML patients and that is required for proliferation of primary CML cells and CML cell lines sensitive and resistant to the TKI imatinib. We demonstrate that depletion of METTL3 strongly impairs global translation efficiency. In particular, our data show that METTL3 is crucial for the expression of genes involved in ribosome biogenesis and translation. Specifically, we found that METTL3 directly regulates the level of PES1 protein identified as an oncogene in several tumors. We propose a model in which nuclear METTL3/METTL14 methyltransferase complex modified nascent transcripts whose translation is enhanced by cytoplasmic localization of METTL3, independently from its catalytic activity. In conclusion, our results point to METTL3 as a novel relevant oncogene in CML and as a promising therapeutic target for TKI resistant CML.


Asunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Metiltransferasas/metabolismo , Biosíntesis de Proteínas , Adenosina/análogos & derivados , Adenosina/metabolismo , Catálisis , Línea Celular Tumoral , Núcleo Celular/metabolismo , Proliferación Celular , Supervivencia Celular , Resistencia a Antineoplásicos/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Humanos , Mesilato de Imatinib/farmacología , Mesilato de Imatinib/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Modelos Biológicos , Proteínas Proto-Oncogénicas c-myc/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Regulación hacia Arriba
16.
Cell Death Dis ; 11(11): 959, 2020 11 07.
Artículo en Inglés | MEDLINE | ID: mdl-33161413

RESUMEN

Long non-coding RNAs are emerging as new molecular players involved in many biological processes, such as proliferation, apoptosis, cell cycle, migration, and differentiation. Their aberrant expression has been reported in variety of diseases. The aim of this study is the identification and functional characterization of clinically relevant lncRNAs responsible for the inhibition of miR-145-5p, a key tumor suppressor in thymic epithelial tumors (TETs). Starting from gene expression analysis by microarray in a cohort of fresh frozen thymic tumors and normal tissues, we identified LINC00174 as upregulated in TET. Interestingly, LINC00174 expression is positively correlated with a 5-genes signature in TETs. Survival analyses, performed on the TCGA dataset, showed that LINC00174 and its associated 5-genes signature are prognostic in TETs. Specifically, we show that LINC00174 favors the expression of SYBU, FEM1B, and SCD5 genes by sponging miR-145-5p, a well-known tumor suppressor microRNA downregulated in a variety of tumors, included TETs. Functionally, LINC00174 impacts on cell migration and lipid metabolism. Specifically, SCD5, one of the LINC00174-associated genes, is implicated in the control of lipid metabolism and promotes thymic cancer cells migration. Our study highlights that LINC00174 and its associated gene signature are relevant prognostic indicators in TETs. Of note, we here show that a key controller of lipid metabolism, SCD5, augments the migration ability of TET cells, creating a link between lipids and motility, and highlighting these pathways as relevant targets for the development of novel therapeutic approaches for TET.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Proteínas Portadoras/metabolismo , Proteínas de Ciclo Celular/metabolismo , Movimiento Celular , Regulación Neoplásica de la Expresión Génica , Metabolismo de los Lípidos , Neoplasias Glandulares y Epiteliales/patología , ARN Largo no Codificante/genética , Neoplasias del Timo/patología , Apoptosis , Biomarcadores de Tumor/genética , Proteínas Portadoras/genética , Proteínas de Ciclo Celular/genética , Proliferación Celular , Perfilación de la Expresión Génica , Humanos , Neoplasias Glandulares y Epiteliales/genética , Neoplasias Glandulares y Epiteliales/metabolismo , Pronóstico , Tasa de Supervivencia , Neoplasias del Timo/genética , Neoplasias del Timo/metabolismo , Células Tumorales Cultivadas
17.
Biochim Biophys Acta ; 1783(4): 578-88, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-18241675

RESUMEN

When small B lymphocytes bind their cognate antigens in the context of suitable signals, a dramatic differentiation program is activated that leads to the formation of plasma cells. These are short-lived specialized elements, each capable of secreting several thousands antibodies per second. The massive increase in Ig synthesis and transport entails a dramatic architectural and functional metamorphosis that involves the development of the endoplasmic reticulum (ER) and secretory organelles. Massive Ig secretion poses novel metabolic requirements, particularly for what concerns aminoacid import, ATP synthesis and redox homeostasis. Ig H and L chains enter the ER in the reduced state, to be rapidly oxidised mainly via protein driven relays based on the resident enzymes PDI and Ero1. How do plasma cells cope with the ensuing metabolic and redox stresses? In this essay, we discuss the physiological implications that increased Ig production could have in the control of plasma cell generation, function and lifespan, with emphasis on the potential role of ROS generation in mitochondria and ER.


Asunto(s)
Linfocitos B/citología , Diferenciación Celular , Retículo Endoplásmico/fisiología , Células Plasmáticas/citología , Animales , Formación de Anticuerpos , Linfocitos B/inmunología , Humanos , Oxidación-Reducción , Células Plasmáticas/inmunología , Pliegue de Proteína
18.
Sci Rep ; 9(1): 11749, 2019 08 13.
Artículo en Inglés | MEDLINE | ID: mdl-31409839

RESUMEN

In this work, we have exploited the unique properties of a chimeric archaeal-human ferritin to encapsulate, deliver and release cytochrome c and induce apoptosis in a myeloid leukemia cell line. The chimeric protein combines the versatility in 24-meric assembly and cargo incorporation capability of Archaeglobus fulgidus ferritin with specific binding of human H ferritin to CD71, the "heavy duty" carrier responsible for transferrin-iron uptake. Delivery of ferritin-encapsulated cytochrome C to the Acute Promyelocytic Leukemia (APL) NB4 cell line, highly resistant to transfection by conventional methods, was successfully achieved in vitro. The effective liberation of cytochrome C within the cytosolic environment, demonstrated by double fluorescent labelling, induced apoptosis in the cancer cells.


Asunto(s)
Citocromos c/metabolismo , Ferritinas/administración & dosificación , Leucemia Promielocítica Aguda/metabolismo , Nanoestructuras , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Humanos , Leucemia Promielocítica Aguda/patología , Tretinoina/farmacología
19.
Cancers (Basel) ; 12(1)2019 Dec 30.
Artículo en Inglés | MEDLINE | ID: mdl-31905996

RESUMEN

: NRF2 (NF-E2 p45-related factor 2) orchestrates cellular adaptive responses to stress. Its quantity and subcellular location is controlled through a complex network and its activity increases during redox perturbation, inflammation, growth factor stimulation, and energy fluxes. Even before all-trans retinoic acid (ATRA) treatment era it was a common experience that acute promyelocytic leukemia (APL) cells are highly sensitive to first line chemotherapy. Since we demonstrated how high doses of ascorbate (ASC) preferentially kill leukemic blast cells from APL patients, we aimed to define the underlying mechanism and found that promyelocytic leukemia/retinoic acid receptor α (PML/RARa) inhibits NRF2 function, impedes its transfer to the nucleus and enhances its degradation in the cytoplasm. Such loss of NRF2 function alters cell metabolism, demarcating APL tissue from both normal promyelocytes and other acute myeloide leukemia (AML) blast cells. Resistance to ATRA/arsenic trioxide (ATO) treatment is rare but grave and the metabolically-oriented treatment with high doses of ASC, which is highly effective on APL cells and harmless on normal hematopoietic stem cells (HSCs), could be of use in preventing clonal evolution and in rescuing APL-resistant patients.

20.
Blood Adv ; 3(24): 4155-4160, 2019 12 23.
Artículo en Inglés | MEDLINE | ID: mdl-31834935

RESUMEN

Acute myeloid leukemia (AML) is often characterized by the expression of fusion or mutant proteins that cause impaired differentiation and enhanced proliferation and survival. The presence of mutant proteins prone to misfolding can render the cells sensitive to endoplasmic reticulum (ER) stress and oxidative stress that could otherwise be overcome. Here, we show that the triple combination of the differentiating agent retinoic acid (RA), the ER stress-inducing drug tunicamycin (Tm), and arsenic trioxide (ATO), able to generate oxidative stress, leads to the death of AML cell lines expressing fusion proteins involving the gene MLL and the internal tandem duplication (ITD) in the FLT3 tyrosine kinase receptor. Importantly, the combination of RA, Tm, and ATO decreased the colony-forming capacity of primary leukemic blasts bearing the FLT-ITD mutation without affecting healthy hematopoietic progenitor cells. We demonstrate in cell lines that combination of these drugs generates ER and oxidative stresses and impairs maturation and causes accumulation of FLT3 protein in the ER. Our data provide a proof of concept that low amounts of drugs that generate ER and oxidative stresses combined with RA could be an effective targeted therapy to hit AML cells characterized by MLL fusion proteins and FLT3-ITD mutation.


Asunto(s)
Muerte Celular , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Estrés Oxidativo , Secuencias Repetidas en Tándem , Tretinoina/farmacología , Respuesta de Proteína Desplegada , Tirosina Quinasa 3 Similar a fms/genética , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Estrés del Retículo Endoplásmico/efectos de los fármacos , Duplicación de Gen , Humanos , Leucemia Mieloide Aguda/patología , Estrés Oxidativo/efectos de los fármacos , Respuesta de Proteína Desplegada/efectos de los fármacos , Tirosina Quinasa 3 Similar a fms/metabolismo
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