Complete Acid Ceramidase ablation prevents cancer-initiating cell formation in melanoma cells

Abstract Acid ceramidase (AC) is a lysosomal cysteine hydrolase that catalyzes the conversion of ceramide into fatty acid and sphingosine. This reaction lowers intracellular ceramide levels and concomitantly generates sphingosine used for sphingosine-1-phosphate (S1P) production. Since increases in...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Michele Lai, Natalia Realini, Marco La Ferla, Ilaria Passalacqua, Giulia Matteoli, Anand Ganesan, Mauro Pistello, Chiara Maria Mazzanti, Daniele Piomelli
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/180c41426d6d457d925b68d89b55c644
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:180c41426d6d457d925b68d89b55c644
record_format	dspace
spelling	oai:doaj.org-article:180c41426d6d457d925b68d89b55c6442021-12-02T11:40:13ZComplete Acid Ceramidase ablation prevents cancer-initiating cell formation in melanoma cells10.1038/s41598-017-07606-w2045-2322https://doaj.org/article/180c41426d6d457d925b68d89b55c6442017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-07606-whttps://doaj.org/toc/2045-2322Abstract Acid ceramidase (AC) is a lysosomal cysteine hydrolase that catalyzes the conversion of ceramide into fatty acid and sphingosine. This reaction lowers intracellular ceramide levels and concomitantly generates sphingosine used for sphingosine-1-phosphate (S1P) production. Since increases in ceramide and consequent decreases of S1P reduce proliferation of various cancers, AC might offer a new target for anti-tumor therapy. Here we used CrispR-Cas9-mediated gene editing to delete the gene encoding for AC, ASAH1, in human A375 melanoma cells. ASAH1-null clones show significantly greater accumulation of long-chain saturated ceramides that are substrate for AC. As seen with administration of exogenous ceramide, AC ablation blocks cell cycle progression and accelerates senescence. Importantly, ASAH1-null cells also lose the ability to form cancer-initiating cells and to undergo self-renewal, which is suggestive of a key role for AC in maintaining malignancy and self-renewal of invasive melanoma cells. The results suggest that AC inhibitors might find therapeutic use as adjuvant therapy for advanced melanoma.Michele LaiNatalia RealiniMarco La FerlaIlaria PassalacquaGiulia MatteoliAnand GanesanMauro PistelloChiara Maria MazzantiDaniele PiomelliNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Michele Lai Natalia Realini Marco La Ferla Ilaria Passalacqua Giulia Matteoli Anand Ganesan Mauro Pistello Chiara Maria Mazzanti Daniele Piomelli Complete Acid Ceramidase ablation prevents cancer-initiating cell formation in melanoma cells
description	Abstract Acid ceramidase (AC) is a lysosomal cysteine hydrolase that catalyzes the conversion of ceramide into fatty acid and sphingosine. This reaction lowers intracellular ceramide levels and concomitantly generates sphingosine used for sphingosine-1-phosphate (S1P) production. Since increases in ceramide and consequent decreases of S1P reduce proliferation of various cancers, AC might offer a new target for anti-tumor therapy. Here we used CrispR-Cas9-mediated gene editing to delete the gene encoding for AC, ASAH1, in human A375 melanoma cells. ASAH1-null clones show significantly greater accumulation of long-chain saturated ceramides that are substrate for AC. As seen with administration of exogenous ceramide, AC ablation blocks cell cycle progression and accelerates senescence. Importantly, ASAH1-null cells also lose the ability to form cancer-initiating cells and to undergo self-renewal, which is suggestive of a key role for AC in maintaining malignancy and self-renewal of invasive melanoma cells. The results suggest that AC inhibitors might find therapeutic use as adjuvant therapy for advanced melanoma.
format	article
author	Michele Lai Natalia Realini Marco La Ferla Ilaria Passalacqua Giulia Matteoli Anand Ganesan Mauro Pistello Chiara Maria Mazzanti Daniele Piomelli
author_facet	Michele Lai Natalia Realini Marco La Ferla Ilaria Passalacqua Giulia Matteoli Anand Ganesan Mauro Pistello Chiara Maria Mazzanti Daniele Piomelli
author_sort	Michele Lai
title	Complete Acid Ceramidase ablation prevents cancer-initiating cell formation in melanoma cells
title_short	Complete Acid Ceramidase ablation prevents cancer-initiating cell formation in melanoma cells
title_full	Complete Acid Ceramidase ablation prevents cancer-initiating cell formation in melanoma cells
title_fullStr	Complete Acid Ceramidase ablation prevents cancer-initiating cell formation in melanoma cells
title_full_unstemmed	Complete Acid Ceramidase ablation prevents cancer-initiating cell formation in melanoma cells
title_sort	complete acid ceramidase ablation prevents cancer-initiating cell formation in melanoma cells
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/180c41426d6d457d925b68d89b55c644
work_keys_str_mv	AT michelelai completeacidceramidaseablationpreventscancerinitiatingcellformationinmelanomacells AT nataliarealini completeacidceramidaseablationpreventscancerinitiatingcellformationinmelanomacells AT marcolaferla completeacidceramidaseablationpreventscancerinitiatingcellformationinmelanomacells AT ilariapassalacqua completeacidceramidaseablationpreventscancerinitiatingcellformationinmelanomacells AT giuliamatteoli completeacidceramidaseablationpreventscancerinitiatingcellformationinmelanomacells AT anandganesan completeacidceramidaseablationpreventscancerinitiatingcellformationinmelanomacells AT mauropistello completeacidceramidaseablationpreventscancerinitiatingcellformationinmelanomacells AT chiaramariamazzanti completeacidceramidaseablationpreventscancerinitiatingcellformationinmelanomacells AT danielepiomelli completeacidceramidaseablationpreventscancerinitiatingcellformationinmelanomacells
_version_	1718395687655178240

Complete Acid Ceramidase ablation prevents cancer-initiating cell formation in melanoma cells

Ejemplares similares