Knocking out alpha-synuclein in melanoma cells dysregulates cellular iron metabolism and suppresses tumor growth

Abstract The protein alpha-synuclein (α-syn) is unusual because, depending on its conformation and the type of cell in which it is expressed, it is pro-death or pro-survival, triggering neurodegeneration in Parkinson’s disease and enhancing cell survival of some melanomas. To probe the function of α...

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Autores principales:	Sahar Shekoohi, Santhanasabapathy Rajasekaran, Dhaval Patel, Shu Yang, Wang Liu, Shile Huang, Xiuping Yu, Stephan N. Witt
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/97f081a407604a379445ec7aeb245044
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spelling	oai:doaj.org-article:97f081a407604a379445ec7aeb2450442021-12-02T13:34:46ZKnocking out alpha-synuclein in melanoma cells dysregulates cellular iron metabolism and suppresses tumor growth10.1038/s41598-021-84443-y2045-2322https://doaj.org/article/97f081a407604a379445ec7aeb2450442021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-84443-yhttps://doaj.org/toc/2045-2322Abstract The protein alpha-synuclein (α-syn) is unusual because, depending on its conformation and the type of cell in which it is expressed, it is pro-death or pro-survival, triggering neurodegeneration in Parkinson’s disease and enhancing cell survival of some melanomas. To probe the function of α-syn in melanoma, we used CRISPR/Cas9 to knockout SNCA, the gene that codes for α-syn, in SK-Mel-28 melanoma cells. The SNCA-knockout clones in culture exhibited a decrease in the transferrin receptor 1 (TfR1), an increase in ferritin, an increase of reactive oxygen species and proliferated slower than control cells. These SNCA-knockout clones grafted into SCID mice grew significantly slower than the SK-Mel-28 control cells that expressed α-syn. In the excised SNCA-knockout xenografts, TfR1 decreased 3.3-fold, ferritin increased 6.2-fold, the divalent metal ion transporter 1 (DMT1) increased threefold, and the iron exporter ferroportin (FPN1) decreased twofold relative to control xenografts. The excised SNCA-KO tumors exhibited significantly more ferric iron and TUNEL staining relative to the control melanoma xenografts. Collectively, depletion of α-syn in SK-Mel-28 cells dysregulates cellular iron metabolism, especially in xenografts, yielding melanoma cells that are deficient in TfR1 and FPN1, that accumulate ferric iron and ferritin, and that undergo apoptosis relative to control cells expressing α-syn.Sahar ShekoohiSanthanasabapathy RajasekaranDhaval PatelShu YangWang LiuShile HuangXiuping YuStephan N. WittNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sahar Shekoohi Santhanasabapathy Rajasekaran Dhaval Patel Shu Yang Wang Liu Shile Huang Xiuping Yu Stephan N. Witt Knocking out alpha-synuclein in melanoma cells dysregulates cellular iron metabolism and suppresses tumor growth
description	Abstract The protein alpha-synuclein (α-syn) is unusual because, depending on its conformation and the type of cell in which it is expressed, it is pro-death or pro-survival, triggering neurodegeneration in Parkinson’s disease and enhancing cell survival of some melanomas. To probe the function of α-syn in melanoma, we used CRISPR/Cas9 to knockout SNCA, the gene that codes for α-syn, in SK-Mel-28 melanoma cells. The SNCA-knockout clones in culture exhibited a decrease in the transferrin receptor 1 (TfR1), an increase in ferritin, an increase of reactive oxygen species and proliferated slower than control cells. These SNCA-knockout clones grafted into SCID mice grew significantly slower than the SK-Mel-28 control cells that expressed α-syn. In the excised SNCA-knockout xenografts, TfR1 decreased 3.3-fold, ferritin increased 6.2-fold, the divalent metal ion transporter 1 (DMT1) increased threefold, and the iron exporter ferroportin (FPN1) decreased twofold relative to control xenografts. The excised SNCA-KO tumors exhibited significantly more ferric iron and TUNEL staining relative to the control melanoma xenografts. Collectively, depletion of α-syn in SK-Mel-28 cells dysregulates cellular iron metabolism, especially in xenografts, yielding melanoma cells that are deficient in TfR1 and FPN1, that accumulate ferric iron and ferritin, and that undergo apoptosis relative to control cells expressing α-syn.
format	article
author	Sahar Shekoohi Santhanasabapathy Rajasekaran Dhaval Patel Shu Yang Wang Liu Shile Huang Xiuping Yu Stephan N. Witt
author_facet	Sahar Shekoohi Santhanasabapathy Rajasekaran Dhaval Patel Shu Yang Wang Liu Shile Huang Xiuping Yu Stephan N. Witt
author_sort	Sahar Shekoohi
title	Knocking out alpha-synuclein in melanoma cells dysregulates cellular iron metabolism and suppresses tumor growth
title_short	Knocking out alpha-synuclein in melanoma cells dysregulates cellular iron metabolism and suppresses tumor growth
title_full	Knocking out alpha-synuclein in melanoma cells dysregulates cellular iron metabolism and suppresses tumor growth
title_fullStr	Knocking out alpha-synuclein in melanoma cells dysregulates cellular iron metabolism and suppresses tumor growth
title_full_unstemmed	Knocking out alpha-synuclein in melanoma cells dysregulates cellular iron metabolism and suppresses tumor growth
title_sort	knocking out alpha-synuclein in melanoma cells dysregulates cellular iron metabolism and suppresses tumor growth
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/97f081a407604a379445ec7aeb245044
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Knocking out alpha-synuclein in melanoma cells dysregulates cellular iron metabolism and suppresses tumor growth

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