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1. Acyl-CoA synthetase 4 modulates mitochondrial function in breast cancer cells

Author

Yanina Benzo, Jesica G. Prada, Melina A. Dattilo, María Mercedes Bigi, Ana F. Castillo, María Mercedes Mori Sequeiros Garcia, Cecilia Poderoso, and Paula M. Maloberti

Subjects
ACSL4, Acyl-CoA synthetase 4, Mitochondria, Glycolysis, Bioenergetics, Oxygen consumption rate, Science (General), Q1-390, Social sciences (General), H1-99
Abstract

Mitochondria are dynamic organelles that respond to cellular stress through changes in global mass, interconnection, and subcellular location. As mitochondria play an important role in tumor development and progression, alterations in energy metabolism allow tumor cells to survive and spread even in challenging conditions. Alterations in mitochondrial bioenergetics have been recently proposed as a hallmark of cancer, and positive regulation of lipid metabolism constitutes one of the most common metabolic changes observed in tumor cells. Acyl-CoA synthetase 4 (ACSL4) is an enzyme catalyzing the activation of long chain polyunsaturated fatty acids with a strong substrate preference for arachidonic acid (AA). High ACSL4 expression has been related to aggressive cancer phenotypes, including breast cancer, and its overexpression has been shown to positively regulate the mammalian Target of Rapamycin (mTOR) pathway, involved in the regulation of mitochondrial metabolism genes. However, little is known about the role of ACSL4 in the regulation of mitochondrial function and metabolism in cancer cells. In this context, our objective was to study whether mitochondrial function and metabolism, processes usually altered in tumors, are modulated by ACSL4 in breast cancer cells. Using ACSL4 overexpression in MCF-7 cells, we demonstrate that this enzyme can increase the mRNA and protein levels of essential mitochondrial regulatory proteins such as nuclear respiratory factor 1 (NRF-1), voltage-dependent anion channel 1 (VDAC1) and respiratory chain Complex III. Furthermore, respiratory parameters analysis revealed an increase in oxygen consumption rate (OCR) and in spare respiratory capacity (SRC), among others. ACSL4 knockdown in MDA-MB-231 cells led to the decrease in OCR and in SCR, supporting the role of ACSL4 in the regulation of mitochondrial bioenergetics. Moreover, ACSL4 overexpression induced an increase in glycolytic function, in keeping with an increase in mitochondrial respiratory activity. Finally, there was a decrease in mitochondrial mass detected in cells that overexpressed ACSL4, while the knockdown of ACSL4 expression in MDA-MB-231 cells showed the opposite effect. Altogether, these results unveil the role of ACSL4 in mitochondrial function and metabolism and expand the knowledge of ACSL4 participation in pathological processes such as breast cancer.

Published
2024
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2. Angiotensin II-upregulated MAP kinase phosphatase-3 modulates FOXO1 and p21 in adrenocortical H295R cells

Author

M. Mercedes Mori Sequeiros Garcia, Juan M. Cohen Sabban, Melina A. Dattilo, Pablo G. Mele, Silvana I. Nudler, Carlos F. Mendez, Paula M. Maloberti, and Cristina Paz

Subjects
Cell biology, Proteins, Biochemistry, Molecular biology, Biomolecules, MKP-3, Science (General), Q1-390, Social sciences (General), H1-99
Abstract

MAPK phosphatases (MKP) downregulate the activity of mitogen-activated protein kinases (MAPK), such as ERK1/2, and modulate the processes regulated by these kinases. ERK1/2 participate in a wide range of processes including tissue-specific hormone-stimulated steroidogenesis. H295R cells are a suitable model for the study of human adrenal cortex functions, particularly steroid synthesis, and respond to angiotensin II (Ang II) triggering ERK1/2 phosphorylation in a transient fashion. MKP-3 dephosphorylates ERK1/2 and, as recently reported, forkhead box protein 1 (FOXO1). Here, we analyzed MKP-3 expression in H295R cells and its putative regulation by Ang II. Results showed the expression of MKP-3 full length (L) and a short splice variant (S), and the upregulation of both isoforms by Ang II. L and S messenger and protein levels increased 30 min after Ang II stimulation and declined over the next 3 h, a temporal frame compatible with ERK1/2 dephosphorylation. In addition, FOXO1 activation is known to include its dephosphorylation and nuclear translocation. Therefore, we analyzed the effect of Ang II on FOXO1 modulation. Ang II induced FOXO1 transient phosphorylation and translocation and also the induction of p21, a FOXO1-dependent gene, whereas MKP-3 knock-down reduced both FOXO1 translocation and p21 induction. These data suggest that, through MKP-3, Ang II counteracts its own effects on ERK1/2 activity and also triggers the activation of FOXO-1 and the induction of cell cycle inhibitor p21. Taken together, the current findings reveal the participation of MKP-3 not only in turn–off but also in turn-on signals which control important cellular processes.

Published
2020
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3. New inhibitor targeting Acyl-CoA synthetase 4 reduces breast and prostate tumor growth, therapeutic resistance and steroidogenesis

Author

Paula Maloberti, María T. Torres, Facundo José Salinas, Natalia Raquel Salvetti, Pablo Lorenzano Menna, Graciela Caroca, Daniel E. Gomez, Ulises Daniel Orlando, María Mercedes Bigi, Hugo Hector Ortega, Jesica Giselle Prada, Ana Fernanda Castillo, Juan B. Rodriguez, Angela Rosario Solano, Melina Andrea Dattilo, Belkis Ester Marelli, Mayra Agustina Ríos Medrano, Ernesto J. Podestá, Sebastián Indo, Sergio H. Szajnman, and Héctor R. Contreras

Subjects
Male, Mice, Nude, Breast Neoplasms, Isozyme, ACSL4, Mice, 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, Cell Movement, Prostate, Cell Line, Tumor, Coenzyme A Ligases, purl.org/becyt/ford/3.2 [https], TRIPLE NEGATIVE BREAST CANCER, medicine, Animals, Humans, CASTRATION RESISTANT PROSTATE CANCER, Enzyme Inhibitors, Molecular Biology, Triple-negative breast cancer, Cell Proliferation, Pharmacology, Mice, Inbred BALB C, 0303 health sciences, Binding Sites, Chemistry, Cell growth, 030302 biochemistry & molecular biology, Prostatic Neoplasms, ANTI-HORMONE TREATMENT RESISTANCE, purl.org/becyt/ford/3.1 [https], Cell Biology, Xenograft Model Antitumor Assays, Molecular Docking Simulation, medicine.anatomical_structure, Drug Resistance, Neoplasm, Docking (molecular), Cancer research, Molecular Medicine, Female, Steroids, purl.org/becyt/ford/3 [https], Arachidonic acid, CHEMOTHERAPY RESISTANCE, Signal transduction
Abstract

Acyl-CoA synthetase 4 (ACSL4) is an isoenzyme of the fatty acid ligase-coenzyme-A family taking part in arachidonic acid metabolism and steroidogenesis. ACSL4 is involved in the development of tumor aggressiveness in breast and prostate tumors through the regulation of various signal transduction pathways. Here, a bioinformatics analysis shows that the ACSL4 gene expression and proteomic signatures obtained using a cell model was also observed in tumor samples from breast and cancer patients. A well-validated ACSL4 inhibitor, however, has not been reported hindering the full exploration of this promising target and its therapeutic application on cancer and steroidogenesis inhibition. In this study, ACSL4 inhibitor PRGL493 was identified using a homology model for ACSL4 and docking based virtual screening. PRGL493 was then chemically characterized through nuclear magnetic resonance and mass spectroscopy. The inhibitory activity was demonstrated through the inhibition of arachidonic acid transformation into arachidonoyl-CoA using the recombinant enzyme and cellular models. The compound blocked cell proliferation and tumor growth in both breast and prostate cellular and animal models and sensitized tumor cells to chemotherapeutic and hormonal treatment. Moreover, PGRL493 inhibited de novo steroid synthesis in testis and adrenal cells, in a mouse model and in prostate tumor cells. This work provides proof of concept for the potential application of PGRL493 in clinical practice. Also, these findings may prove key to therapies aiming at the control of tumor growth and drug resistance in tumors which express ACSL4 and depend on steroid synthesis. Fil: Castillo, Ana Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina Fil: Orlando, Ulises Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina Fil: Maloberti, Paula Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina Fil: Prada, Jesica Giselle. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina Fil: Dattilo, Melina Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina Fil: Solano, Angela Rosario. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina Fil: Bigi, Maria de Las Mercedes. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina Fil: Ríos Medrano, Mayra Agustina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina Fil: Torres, María T.. Universidad de Chile. Facultad de Medicina.; Chile Fil: Indo, Sebastián. Universidad de Chile. Facultad de Medicina.; Chile Fil: Caroca, Graciela. Universidad de Chile. Facultad de Medicina.; Chile Fil: Contreras, Hector R.. Universidad de Chile. Facultad de Medicina.; Chile Fil: Marelli, Belkis Ester. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Ciencias Veterinarias del Litoral. Universidad Nacional del Litoral. Facultad de Ciencias Veterinarias. Instituto de Ciencias Veterinarias del Litoral; Argentina Fil: Salinas, Facundo José. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Ciencias Veterinarias del Litoral. Universidad Nacional del Litoral. Facultad de Ciencias Veterinarias. Instituto de Ciencias Veterinarias del Litoral; Argentina Fil: Salvetti, Natalia Raquel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Ciencias Veterinarias del Litoral. Universidad Nacional del Litoral. Facultad de Ciencias Veterinarias. Instituto de Ciencias Veterinarias del Litoral; Argentina Fil: Ortega, Hugo Hector. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Ciencias Veterinarias del Litoral. Universidad Nacional del Litoral. Facultad de Ciencias Veterinarias. Instituto de Ciencias Veterinarias del Litoral; Argentina Fil: Lorenzano Menna, Pablo. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Szajnman, Sergio Hernan. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina Fil: Gómez, Daniel Eduardo. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina Fil: Rodriguez, Juan Bautista. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina Fil: Podesta, Ernesto Jorge. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina

Published
2020
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4. Regulatory mechanisms leading to differential Acyl-CoA synthetase 4 expression in breast cancer cells

Author

Paula Maloberti, Melina Andrea Dattilo, Ernesto J. Podestá, Yanina Benzo, Ulises Daniel Orlando, Lucía Manuela Herrera, Jesica Giselle Prada, and Ana Fernanda Castillo

Subjects
0301 basic medicine, Sp1 Transcription Factor, Transcriptional regulatory elements, estrogen-related receptor alpha, lcsh:Medicine, Triple Negative Breast Neoplasms, Biology, Article, purl.org/becyt/ford/1 [https], Ciencias Biológicas, 03 medical and health sciences, Estrogen-related receptor alpha, 0302 clinical medicine, Breast cancer, estrogen receptor alpha, Cell Line, Tumor, Coenzyme A Ligases, Humans, E2F, Receptor, Promoter Regions, Genetic, purl.org/becyt/ford/1.6 [https], lcsh:Science, Transcription factor, Triple-negative breast cancer, Orphan receptor, Multidisciplinary, Cell growth, lcsh:R, Estrogen Receptor alpha, Nuclear Receptor Subfamily 1, Group F, Member 1, Bioquímica y Biología Molecular, E2F Transcription Factors, Up-Regulation, Gene Expression Regulation, Neoplastic, 030104 developmental biology, triple negative breast cancer, Cancer research, MCF-7 Cells, Mutagenesis, Site-Directed, Female, lcsh:Q, Estrogen receptor alpha, human ACSL4 promoter, 030217 neurology & neurosurgery, CIENCIAS NATURALES Y EXACTAS
Abstract

Acyl-CoA synthetase 4 (ACSL4) overexpression plays a causal role in the aggressiveness of triple negative breast cancer. In turn, a negative correlation has been established between ACSL4 and estrogen receptor alpha (ERα) expression. However, the upstream regulatory mechanisms leading to differential ACSL4 expression between triple negative breast cancer and ERα-positive cells remained unknown. We performed the characterization of the human ACSL4 promoter and the identification of transcription factors involved. Deletional analysis demonstrated the proximal 43 base pairs of the promoter are involved in overexpression. By site directed mutagenesis we describe that retinoid-related orphan receptor alpha (RORα), Sp1 and E2F elements are involved in the promoter activity. We established for the first time that estrogen-related receptor alpha (ERRα) is a transcription factor involved in the higher activation of the human ACSL4 promoter in breast cancer cells. Furthermore, a combination of inhibitors of ACSL4 and ERRα produced a synergistic decrease in MDA-MB-231 cell proliferation. We also demonstrated that ERα restoration in triple negative breast cancer cells downregulates ACSL4 expression. The results presented in this manuscript demonstrated transcriptional mechanism is involved in the different expression of ACSL4 in human breast cancer cell lines of different aggressiveness. Fil: Dattilo, Melina Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina Fil: Benzo, Yanina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina Fil: Herrera, Lucía Manuela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina Fil: Prada, Jesica Giselle. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina Fil: Castillo, Ana Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina Fil: Orlando, Ulises Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina Fil: Podesta, Ernesto Jorge. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina Fil: Maloberti, Paula Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina

Published
2019
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5. Regulation and role of Acyl-CoA synthetase 4 in glial cells

Author

Yanina Benzo, Mercedes Lasaga, Cristina Paz, Melina Andrea Dattilo, Lucía Manuela Herrera, Carla Mariana Caruso, Paula Maloberti, Paula Fernanda Lopez, Jesica Giselle Prada, and Corina I. García

Subjects
0301 basic medicine, Cell type, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Cell, Biochemistry, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Cell Movement, Neurosphere, Cell Line, Tumor, Coenzyme A Ligases, medicine, Cyclic AMP, Gene silencing, Animals, Humans, Cyclic adenosine monophosphate, Molecular Biology, Cell Proliferation, Arachidonic Acid, Chemistry, Steroidogenic acute regulatory protein, Cell Biology, Glioma, Cell biology, Rats, Gene Expression Regulation, Neoplastic, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Astrocytes, Stellation, Molecular Medicine, Neuroglia, Astrocyte
Abstract

Acyl-CoA synthetase 4 (Acsl4), an enzyme involved in arachidonic acid (AA) metabolism, participates in physiological and pathological processes such as steroidogenesis and cancer. The role of Acsl4 in neurons and in nervous system development has also been documented but little is known regarding its functionality in glial cells. In turn, several processes in glial cells, including neurosteroidogenesis, stellation and AA uptake, are regulated by cyclic adenosine monophosphate (cAMP) signal. In this context, the aim of this work was to analyze the expression and functional role of Acsl4 in primary rat astrocyte cultures and in the C6 glioma cell line by chemical inhibition and stable silencing, respectively. Results show that Acsl4 expression was regulated by cAMP in both models and that cAMP stimulation of steroidogenic acute regulatory protein mRNA levels was reduced by Acsl4 inhibition or silencing. Also, Acsl4 inhibition reduced progesterone synthesis stimulated by cAMP and also affected cAMP-induced astrocyte stellation, decreasing process elongation and increasing branching complexity. Similar effects were observed for Acsl4 silencing on cAMP-induced C6 cell morphological shift. Moreover, Acsl4 inhibition and silencing reduced proliferation and migration of both cell types. Acsl4 silencing in C6 cells reduced the capacity for colony proliferation and neurosphere formation, the latter ability also being abolished by Acsl4 inhibition. In sum, this work presents novel evidence of Acsl4 involvement in neurosteroidogenesis and the morphological changes of glial cells promoted by cAMP. Furthermore, Acsl4 participates in migration and proliferation, also affecting cell self-renewal. Altogether, these findings provide insights into Acsl4 functions in glial cells.

Published
2020

6. Angiotensin II-upregulated MAP kinase phosphatase-3 modulates FOXO1 and p21 in adrenocortical H295R cells

Author

Silvana I. Nudler, Carlos F. Mendez, Cristina Paz, Mercedes Mori Sequeiros García, Pablo G. Mele, Paula Maloberti, Juan M. Cohen Sabban, and Melina Andrea Dattilo

Subjects
0301 basic medicine, MAPK/ERK pathway, Cell biology, endocrine system, P21, Molecular biology, DUSP6, FOXO1, Biochemistry, Article, Ciencias Biológicas, purl.org/becyt/ford/1 [https], Dephosphorylation, 03 medical and health sciences, 0302 clinical medicine, lcsh:Social sciences (General), lcsh:Science (General), purl.org/becyt/ford/1.6 [https], H295R, Biomolecules, MKP-3, Multidisciplinary, p21, ERK1/2, biology, ANGIOTENSIN II, Kinase, Chemistry, Proteins, Bioquímica y Biología Molecular, MAP KINASE PHOSPHATASE 3, Angiotensin II, 030104 developmental biology, biology.protein, MAP kinase phosphatase, Phosphorylation, lcsh:H1-99, CIENCIAS NATURALES Y EXACTAS, hormones, hormone substitutes, and hormone antagonists, 030217 neurology & neurosurgery, lcsh:Q1-390
Abstract

MAPK phosphatases (MKP) downregulate the activity of mitogen-activated protein kinases (MAPK), such as ERK1/2, and modulate the processes regulated by these kinases. ERK1/2 participate in a wide range of processes including tissue-specific hormone-stimulated steroidogenesis. H295R cells are a suitable model for the study of human adrenal cortex functions, particularly steroid synthesis, and respond to angiotensin II (Ang II) triggering ERK1/2 phosphorylation in a transient fashion. MKP-3 dephosphorylates ERK1/2 and, as recently reported, forkhead box protein 1 (FOXO1). Here, we analyzed MKP-3 expression in H295R cells and its putative regulation by Ang II. Results showed the expression of MKP-3 full length (L) and a short splice variant (S), and the upregulation of both isoforms by Ang II. L and S messenger and protein levels increased 30 min after Ang II stimulation and declined over the next 3 h, a temporal frame compatible with ERK1/2 dephosphorylation. In addition, FOXO1 activation is known to include its dephosphorylation and nuclear translocation. Therefore, we analyzed the effect of Ang II on FOXO1 modulation. Ang II induced FOXO1 transient phosphorylation and translocation and also the induction of p21, a FOXO1-dependent gene, whereas MKP-3 knock-down reduced both FOXO1 translocation and p21 induction. These data suggest that, through MKP-3, Ang II counteracts its own effects on ERK1/2 activity and also triggers the activation of FOXO-1 and the induction of cell cycle inhibitor p21. Taken together, the current findings reveal the participation of MKP-3 not only in turn–off but also in turn-on signals which control important cellular processes., Cell biology; Proteins; Biochemistry; Molecular biology; Biomolecules; MKP-3, DUSP6, FOXO1, p21, H295R, ERK1/2

Published
2020
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7. Endothelin 1 and 3 enhance neuronal nitric oxide synthase activity through ETB receptors involving multiple signaling pathways in the rat anterior hypothalamus

Author

Andrea S. Di Nunzio, Marcelo S. Vatta, Liliana G. Bianciotti, Marı́a S. Jaureguiberry, and Melina Andrea Dattilo

Subjects
Male, Agonist, medicine.medical_specialty, Physiology, medicine.drug_class, Nitric Oxide Synthase Type I, Biology, Nitric Oxide, Biochemistry, Nitric oxide, Rats, Sprague-Dawley, Cellular and Molecular Neuroscience, chemistry.chemical_compound, Endocrinology, Internal medicine, medicine, Animals, Receptor, education, Endothelin-3, education.field_of_study, Endothelin-1, Antagonist, Receptor, Endothelin B, Endothelin 1, Rats, Endothelin 3, Nitric oxide synthase, Hypothalamus, Anterior, chemistry, biology.protein, Nitric Oxide Synthase, Signal transduction, Signal Transduction
Abstract

We have previously reported that endothelin 1 and 3 (ET-1, ET-3) through the ETB receptor decrease norepinephrine release in the anterior hypothalamus and activate the nitric oxide (NO) pathway. In the present work we sought to establish the receptors and intracellular mechanisms underlying the increase in nitric oxide synthase (NOS) activity stimulated by ET-1 and ET-3 in the rat anterior hypothalamus. Results showed that ETs-stimulated NOS activity was inhibited by a selective ETB antagonist (BQ-788), but not by a selective ETA antagonist (BQ-610). In addition, NOS activity was not altered in the presence of an ETA agonist (sarafotoxin 6b), but it was enhanced in the presence of a ETB agonist (IRL-1620). Both Nomega-nitro-L-arginine methyl ester (NOS inhibitor), and 7-nitroindazole (neuronal NOS inhibitor) diminished ETs-stimulated NOS activity. The stimulatory effect of ETs on NOS activity was inhibited in the presence of PLC, PKC, PKA and CaMK-II inhibitors (U-73122, GF-109203X, H-89 and KN-62, respectively), and the IP3 receptor selective antagonist, 2-APB. Our results showed that both ET-1 and ET-3 modulate neuronal NOS activity through the ETB receptor in the rat anterior hypothalamus involving the participation of the PLC-PKC/IP3 pathway as well as PKA and CaMK-II.

Published
2004
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8. OxeR1 regulates angiotensin II and cAMP-stimulated steroid production in human H295R adrenocortical cells

Author

Melina Andrea Dattilo, Mariana Mabel Muñoz, Isabel Neuman, Fabiana Cornejo Maciel, and Paula Maloberti

Subjects
Male, medicine.medical_specialty, STEROIDOGENESIS, Context (language use), Stimulation, Inflammation, Arachidonic Acids, Biology, Transfection, Biochemistry, Cell Line, Ciencias Biológicas, Mice, Endocrinology, Mediator, Cell surface receptor, cAMP, Internal medicine, medicine, Cyclic AMP, Animals, Humans, Phosphorylation, Extracellular Signal-Regulated MAP Kinases, StAR PROTEIN, Molecular Biology, ANGIOTENSIN II, Angiotensin II, Leydig Cells, Bioquímica y Biología Molecular, Phosphoproteins, Mechanism of action, ERK 1/2, Receptors, Eicosanoid, Adrenal Cortex, Steroids, medicine.symptom, OXOEICOSANOID RECEPTOR OxeR1, CIENCIAS NATURALES Y EXACTAS, Plasmids
Abstract

Hormone-regulated steroidogenesis and StAR protein induction involve the action of lipoxygenated products. The products of 5-lipoxygenase act on inflammation and immunity by stimulation of a membrane receptor called OxeR1. The presence of OxeR1 in other systems has not been described up to date and little is known about its mechanism of action and other functions. In this context, the aim of this study was the identification and characterization of OxeR1 as a mediator of cAMP-dependent and independent pathways. Overexpression of OxeR1 in MA-10 Leydig cells increased cAMP-dependent progesterone production. Angiotensin II and cAMP stimulation of adrenocortical human H295R cells produced an increase in StAR protein induction and steroidogenesis in cells overexpressing OxeR1 as compared to mock-transfected cells. Additionally, activation of OxeR1 caused a time-dependent increase in ERK1/2 phosphorylation. In summary, membrane receptor OxeR1 is involved in StAR protein induction and activation of steroidogenesis triggered by cAMP or angiotensin II, acting, at least in part, through ERK1/2 activation. Fil: Dattilo, Melina Andrea. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Investigaciones Biomedicas; Argentina; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquimica; Argentina Fil: Neuman, Isabel. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Investigaciones Biomedicas; Argentina; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquimica; Argentina Fil: Muñoz, Mariana Mabel. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Investigaciones Biomedicas; Argentina; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquimica; Argentina Fil: Maloberti, Paula Mariana. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Investigaciones Biomedicas; Argentina; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquimica; Argentina Fil: Cornejo Maciel, Fabiana. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Investigaciones Biomedicas; Argentina; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquimica; Argentina

Published
2014

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