Flavonoids increase melanin production and reduce proliferation, migration and invasion of melanoma cells by blocking endolysosomal/melanosomal TPC2

Abstract Two-pore channel 2 (TPC2) resides in endolysosomal membranes but also in lysosome-related organelles such as the melanin producing melanosomes. Gain-of-function polymorphisms in hTPC2 are associated with decreased melanin production and blond hair color. Vice versa genetic ablation of TPC2...

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Autores principales:	Ponsawan Netcharoensirisuk, Carla Abrahamian, Rachel Tang, Cheng-Chang Chen, Anna Scotto Rosato, Wyatt Beyers, Yu-Kai Chao, Antonio Filippini, Santiago Di Pietro, Karin Bartel, Martin Biel, Angelika M. Vollmar, Kaoru Umehara, Wanchai De-Eknamkul, Christian Grimm
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8f4de751c6ed48b481f4c92a2999702f
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spelling	oai:doaj.org-article:8f4de751c6ed48b481f4c92a2999702f2021-12-02T16:45:47ZFlavonoids increase melanin production and reduce proliferation, migration and invasion of melanoma cells by blocking endolysosomal/melanosomal TPC210.1038/s41598-021-88196-62045-2322https://doaj.org/article/8f4de751c6ed48b481f4c92a2999702f2021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-88196-6https://doaj.org/toc/2045-2322Abstract Two-pore channel 2 (TPC2) resides in endolysosomal membranes but also in lysosome-related organelles such as the melanin producing melanosomes. Gain-of-function polymorphisms in hTPC2 are associated with decreased melanin production and blond hair color. Vice versa genetic ablation of TPC2 increases melanin production. We show here an inverse correlation between melanin production and melanoma proliferation, migration, and invasion due to the dual activity of TPC2 in endolysosomes and melanosomes. Our results are supported by both genetic ablation and pharmacological inhibition of TPC2. Mechanistically, our data show that loss/block of TPC2 results in reduced protein levels of MITF, a major regulator of melanoma progression, but an increased activity of the melanin-generating enzyme tyrosinase. TPC2 inhibition thus provides a twofold benefit in melanoma prevention and treatment by increasing, through interference with tyrosinase activity, the synthesis of UV blocking melanin in melanosomes and by decreasing MITF-driven melanoma progression by increased GSK3β-mediated MITF degradation.Ponsawan NetcharoensirisukCarla AbrahamianRachel TangCheng-Chang ChenAnna Scotto RosatoWyatt BeyersYu-Kai ChaoAntonio FilippiniSantiago Di PietroKarin BartelMartin BielAngelika M. VollmarKaoru UmeharaWanchai De-EknamkulChristian GrimmNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ponsawan Netcharoensirisuk Carla Abrahamian Rachel Tang Cheng-Chang Chen Anna Scotto Rosato Wyatt Beyers Yu-Kai Chao Antonio Filippini Santiago Di Pietro Karin Bartel Martin Biel Angelika M. Vollmar Kaoru Umehara Wanchai De-Eknamkul Christian Grimm Flavonoids increase melanin production and reduce proliferation, migration and invasion of melanoma cells by blocking endolysosomal/melanosomal TPC2
description	Abstract Two-pore channel 2 (TPC2) resides in endolysosomal membranes but also in lysosome-related organelles such as the melanin producing melanosomes. Gain-of-function polymorphisms in hTPC2 are associated with decreased melanin production and blond hair color. Vice versa genetic ablation of TPC2 increases melanin production. We show here an inverse correlation between melanin production and melanoma proliferation, migration, and invasion due to the dual activity of TPC2 in endolysosomes and melanosomes. Our results are supported by both genetic ablation and pharmacological inhibition of TPC2. Mechanistically, our data show that loss/block of TPC2 results in reduced protein levels of MITF, a major regulator of melanoma progression, but an increased activity of the melanin-generating enzyme tyrosinase. TPC2 inhibition thus provides a twofold benefit in melanoma prevention and treatment by increasing, through interference with tyrosinase activity, the synthesis of UV blocking melanin in melanosomes and by decreasing MITF-driven melanoma progression by increased GSK3β-mediated MITF degradation.
format	article
author	Ponsawan Netcharoensirisuk Carla Abrahamian Rachel Tang Cheng-Chang Chen Anna Scotto Rosato Wyatt Beyers Yu-Kai Chao Antonio Filippini Santiago Di Pietro Karin Bartel Martin Biel Angelika M. Vollmar Kaoru Umehara Wanchai De-Eknamkul Christian Grimm
author_facet	Ponsawan Netcharoensirisuk Carla Abrahamian Rachel Tang Cheng-Chang Chen Anna Scotto Rosato Wyatt Beyers Yu-Kai Chao Antonio Filippini Santiago Di Pietro Karin Bartel Martin Biel Angelika M. Vollmar Kaoru Umehara Wanchai De-Eknamkul Christian Grimm
author_sort	Ponsawan Netcharoensirisuk
title	Flavonoids increase melanin production and reduce proliferation, migration and invasion of melanoma cells by blocking endolysosomal/melanosomal TPC2
title_short	Flavonoids increase melanin production and reduce proliferation, migration and invasion of melanoma cells by blocking endolysosomal/melanosomal TPC2
title_full	Flavonoids increase melanin production and reduce proliferation, migration and invasion of melanoma cells by blocking endolysosomal/melanosomal TPC2
title_fullStr	Flavonoids increase melanin production and reduce proliferation, migration and invasion of melanoma cells by blocking endolysosomal/melanosomal TPC2
title_full_unstemmed	Flavonoids increase melanin production and reduce proliferation, migration and invasion of melanoma cells by blocking endolysosomal/melanosomal TPC2
title_sort	flavonoids increase melanin production and reduce proliferation, migration and invasion of melanoma cells by blocking endolysosomal/melanosomal tpc2
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/8f4de751c6ed48b481f4c92a2999702f
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Flavonoids increase melanin production and reduce proliferation, migration and invasion of melanoma cells by blocking endolysosomal/melanosomal TPC2

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