Combination of anti-proliferative signalling activation for the treatment of pituitary tumors

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Current therapies for pituitary adenomas focus on stimulating somatostatin receptors (SSTRs) that inhibit cell proliferation and hormone secretion. However, half of patients become resistant to the SST analogue Octreotide (OCT), with the search for alternative strategies that overcome such resistanc...

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Autores principales: Picech, F, Sosa, L, Mukdsi, J, Torres, A, Petiti, J
Formato: Artículo revista
Lenguaje:Español
Publicado: Universidad Nacional Cba. Facultad de Ciencias Médicas. Secretaria de Ciencia y Tecnología 2019
Materias:
pituitary adenomas
SSTR
proliferation
hormone secretion
therapeutic targets
adenomas hipofisiarios
SSTRs
TGFB
Acceso en línea:https://revistas.unc.edu.ar/index.php/med/article/view/26190
Aporte de:
Revistas de la UNC de Universidad Nacional de Córdoba
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record_format ojs
institution Universidad Nacional de Córdoba
institution_str I-10
repository_str R-10
container_title_str Revistas de la UNC
language Español
format Artículo revista
topic pituitary adenomas
SSTR
proliferation
hormone secretion
therapeutic targets
adenomas hipofisiarios
SSTRs
TGFB
spellingShingle pituitary adenomas
SSTR
proliferation
hormone secretion
therapeutic targets
adenomas hipofisiarios
SSTRs
TGFB
Picech, F
Sosa, L
Mukdsi, J
Torres, A
Petiti, J
Combination of anti-proliferative signalling activation for the treatment of pituitary tumors
topic_facet pituitary adenomas
SSTR
proliferation
hormone secretion
therapeutic targets
adenomas hipofisiarios
SSTRs
TGFB
author Picech, F
Sosa, L
Mukdsi, J
Torres, A
Petiti, J
author_facet Picech, F
Sosa, L
Mukdsi, J
Torres, A
Petiti, J
author_sort Picech, F
title Combination of anti-proliferative signalling activation for the treatment of pituitary tumors
title_short Combination of anti-proliferative signalling activation for the treatment of pituitary tumors
title_full Combination of anti-proliferative signalling activation for the treatment of pituitary tumors
title_fullStr Combination of anti-proliferative signalling activation for the treatment of pituitary tumors
title_full_unstemmed Combination of anti-proliferative signalling activation for the treatment of pituitary tumors
title_sort combination of anti-proliferative signalling activation for the treatment of pituitary tumors
description Current therapies for pituitary adenomas focus on stimulating somatostatin receptors (SSTRs) that inhibit cell proliferation and hormone secretion. However, half of patients become resistant to the SST analogue Octreotide (OCT), with the search for alternative strategies that overcome such resistance deserving investigation. Here, we analysed the anti-proliferative TGFβ1 signalling in combination with SST activation as a way to effectively control cell proliferation and hormone secretion. First, the expression of SSTRs (SSTR2 and SSTR5) and TβRs (TβRI, TβRII) were found to be downregulated in different types of human pituitary tumours (6 GH-, 2 ACTH-secreting and 9 non-functioning pituitary adenomas -NFPA), compared to normal pituitaries (n=7) by IHC and western blot, suggesting a (lack of) receptor-mediated hyporesponsiveness. Then, GH3 somatolactotroph NFPA human derived and pituitary tumour cells were treated in vitro with OCT (10 and 100 nM), TGFβ1 (4 mg/ml) or a combination of both stimuli for 24h. The co-incubation of OCT/TGFβ1 increased mRNA expression of TβRI, SSTR2, and SSTR5 (by qPCR), being correlated to a decrease in cell proliferation (Ki67 quantification) and PRL secretion (by RIA) comparing to single treatments. Finally, the transient transfection to overexpress SSTR2 induced a significant decrease in GH3 proliferation, as measured by BrdU incorporation, with an additional reduction when these cell were stimulated with OCT/TGFβ1 combination. These findings suggest a possible crosstalk between somatostatin analogues and TGFβ1 modulating both cell proliferation and hormonal secretion in pituitary adenomas, with such interaction representing a promising approach in the context of tumour resistance.
publisher Universidad Nacional Cba. Facultad de Ciencias Médicas. Secretaria de Ciencia y Tecnología
publishDate 2019
url https://revistas.unc.edu.ar/index.php/med/article/view/26190
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AT sosal combinationofantiproliferativesignallingactivationforthetreatmentofpituitarytumors
AT mukdsij combinationofantiproliferativesignallingactivationforthetreatmentofpituitarytumors
AT torresa combinationofantiproliferativesignallingactivationforthetreatmentofpituitarytumors
AT petitij combinationofantiproliferativesignallingactivationforthetreatmentofpituitarytumors
AT picechf activaciondesenalesantiproliferativasparaeltratamientodetumoreshipofisarios
AT sosal activaciondesenalesantiproliferativasparaeltratamientodetumoreshipofisarios
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last_indexed 2022-08-20T01:27:05Z
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spelling I10-R10-article-261902019-11-11T21:18:27Z Combination of anti-proliferative signalling activation for the treatment of pituitary tumors Activación de señales anti proliferativas para el tratamiento de tumores hipofisarios Picech, F Sosa, L Mukdsi, J Torres, A Petiti, J pituitary adenomas SSTR proliferation hormone secretion therapeutic targets adenomas hipofisiarios SSTRs TGFB Current therapies for pituitary adenomas focus on stimulating somatostatin receptors (SSTRs) that inhibit cell proliferation and hormone secretion. However, half of patients become resistant to the SST analogue Octreotide (OCT), with the search for alternative strategies that overcome such resistance deserving investigation. Here, we analysed the anti-proliferative TGFβ1 signalling in combination with SST activation as a way to effectively control cell proliferation and hormone secretion. First, the expression of SSTRs (SSTR2 and SSTR5) and TβRs (TβRI, TβRII) were found to be downregulated in different types of human pituitary tumours (6 GH-, 2 ACTH-secreting and 9 non-functioning pituitary adenomas -NFPA), compared to normal pituitaries (n=7) by IHC and western blot, suggesting a (lack of) receptor-mediated hyporesponsiveness. Then, GH3 somatolactotroph NFPA human derived and pituitary tumour cells were treated in vitro with OCT (10 and 100 nM), TGFβ1 (4 mg/ml) or a combination of both stimuli for 24h. The co-incubation of OCT/TGFβ1 increased mRNA expression of TβRI, SSTR2, and SSTR5 (by qPCR), being correlated to a decrease in cell proliferation (Ki67 quantification) and PRL secretion (by RIA) comparing to single treatments. Finally, the transient transfection to overexpress SSTR2 induced a significant decrease in GH3 proliferation, as measured by BrdU incorporation, with an additional reduction when these cell were stimulated with OCT/TGFβ1 combination. These findings suggest a possible crosstalk between somatostatin analogues and TGFβ1 modulating both cell proliferation and hormonal secretion in pituitary adenomas, with such interaction representing a promising approach in the context of tumour resistance. Una de las terapias farmacológicas empleada en adenomas hipofisarios está dirigida a la estimulación de receptores de somatostatina (SSTRs), que inhiben la proliferación celular y secreción hormonal. Sin embargo, el 50% de los pacientes manifiestan resistencia al análogo de somatostaina, octreotida (OCT), evidenciando la necesidad de desarrollar estrategias terapéuticas más efectivas. Nuestro objetivo fue analizar si el efecto inhibidor de OCT sobre la proliferación y secreción es potenciado en co-incubación con TGFβ1. Mediante inmunohistoquímica y western blot observamos que la expresión de los receptores SSTRs (SSTR2 y SSTR5) TβRs (TβRI y TβRII) esta disminuida en diferentes tipos de tumores hipofisarios humanos [6 adenomas hipersecretantes de GH, 2 adenomas hipersecretantes de ACTH y 9 adenomas no funciones (NFPA)] en comparación a hipófisis normales (n=7). El trabajo cuenta con la aprobación del comité de ética (Repis N° 37/2014). A continuación, se realizaron cultivos de la línea celular tumoral adenohipofisaria GH3 y cultivo primario de un tumor humano NFPA. Las células fueron tratadas con OCT (10 and 100 nM), TGFβ1 (4 mg/ml) o la combinación de ambos por 24h. La co- incubación de OCT/TGFβ1 disminuyó significativamente la proliferación celular (cuantificada por Ki67) y la secreción de PRL (ensayo de RIA) en comparación a los tratamientos individuales. Además, estos efectos estuvieron asociados a un incremento significativo de los niveles de ARNm de TβRI, SSTR2 y SSTR5 (cuantificados por qPCR). Finalmente, observamos que la sobreexpresión de SSTR2, por transfecciones transientes, disminuyó significativamente la proliferación de células GH3, efecto que fue potenciado cuando las células fueron tratadas con el estímulo combinado OCT/TGFβ1. Estos resultados sugieren un posible crosstalk entre OCT y TGFβ1 que modula la proliferación celular y secreción hormonal, representado una estrategia farmacológica prometedora para pacientes con adenomas hipofisarios resistentes a análogos de SST. Universidad Nacional Cba. Facultad de Ciencias Médicas. Secretaria de Ciencia y Tecnología 2019-11-01 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion application/pdf https://revistas.unc.edu.ar/index.php/med/article/view/26190 Revista de la Facultad de Ciencias Médicas de Córdoba.; 2019: Suplemento JIC XX Revista de la Facultad de Ciencias Médicas de Córdoba; 2019: Suplemento JIC XX Revista da Faculdade de Ciências Médicas de Córdoba; 2019: Suplemento JIC XX 1853-0605 0014-6722 spa https://revistas.unc.edu.ar/index.php/med/article/view/26190/28007 Derechos de autor 2019 Universidad Nacional de Córdoba

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