Estradiol analogs attenuate autophagy, cell migration and invasion by direct and selective inhibition of TRPML1, independent of estrogen receptors

Abstract The cation channel TRPML1 is an important regulator of lysosomal function and autophagy. Loss of TRPML1 is associated with neurodegeneration and lysosomal storage disease, while temporary inhibition of this ion channel has been proposed to be beneficial in cancer therapy. Currently availabl...

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Autores principales:	Philipp Rühl, Anna Scotto Rosato, Nicole Urban, Susanne Gerndt, Rachel Tang, Carla Abrahamian, Charlotte Leser, Jiansong Sheng, Archana Jha, Günter Vollmer, Michael Schaefer, Franz Bracher, Christian Grimm
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4ae8395bdd4d48a1b970609d440ac4a3
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spelling	oai:doaj.org-article:4ae8395bdd4d48a1b970609d440ac4a32021-12-02T14:26:12ZEstradiol analogs attenuate autophagy, cell migration and invasion by direct and selective inhibition of TRPML1, independent of estrogen receptors10.1038/s41598-021-87817-42045-2322https://doaj.org/article/4ae8395bdd4d48a1b970609d440ac4a32021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-87817-4https://doaj.org/toc/2045-2322Abstract The cation channel TRPML1 is an important regulator of lysosomal function and autophagy. Loss of TRPML1 is associated with neurodegeneration and lysosomal storage disease, while temporary inhibition of this ion channel has been proposed to be beneficial in cancer therapy. Currently available TRPML1 channel inhibitors are not TRPML isoform selective and block at least two of the three human isoforms. We have now identified the first highly potent and isoform-selective TRPML1 antagonist, the steroid 17β-estradiol methyl ether (EDME). Two analogs of EDME, PRU-10 and PRU-12, characterized by their reduced activity at the estrogen receptor, have been identified through systematic chemical modification of the lead structure. EDME and its analogs, besides being promising new small molecule tool compounds for the investigation of TRPML1, selectively affect key features of TRPML1 function: autophagy induction and transcription factor EB (TFEB) translocation. In addition, they act as inhibitors of triple-negative breast cancer cell migration and invasion.Philipp RühlAnna Scotto RosatoNicole UrbanSusanne GerndtRachel TangCarla AbrahamianCharlotte LeserJiansong ShengArchana JhaGünter VollmerMichael SchaeferFranz BracherChristian 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 Philipp Rühl Anna Scotto Rosato Nicole Urban Susanne Gerndt Rachel Tang Carla Abrahamian Charlotte Leser Jiansong Sheng Archana Jha Günter Vollmer Michael Schaefer Franz Bracher Christian Grimm Estradiol analogs attenuate autophagy, cell migration and invasion by direct and selective inhibition of TRPML1, independent of estrogen receptors
description	Abstract The cation channel TRPML1 is an important regulator of lysosomal function and autophagy. Loss of TRPML1 is associated with neurodegeneration and lysosomal storage disease, while temporary inhibition of this ion channel has been proposed to be beneficial in cancer therapy. Currently available TRPML1 channel inhibitors are not TRPML isoform selective and block at least two of the three human isoforms. We have now identified the first highly potent and isoform-selective TRPML1 antagonist, the steroid 17β-estradiol methyl ether (EDME). Two analogs of EDME, PRU-10 and PRU-12, characterized by their reduced activity at the estrogen receptor, have been identified through systematic chemical modification of the lead structure. EDME and its analogs, besides being promising new small molecule tool compounds for the investigation of TRPML1, selectively affect key features of TRPML1 function: autophagy induction and transcription factor EB (TFEB) translocation. In addition, they act as inhibitors of triple-negative breast cancer cell migration and invasion.
format	article
author	Philipp Rühl Anna Scotto Rosato Nicole Urban Susanne Gerndt Rachel Tang Carla Abrahamian Charlotte Leser Jiansong Sheng Archana Jha Günter Vollmer Michael Schaefer Franz Bracher Christian Grimm
author_facet	Philipp Rühl Anna Scotto Rosato Nicole Urban Susanne Gerndt Rachel Tang Carla Abrahamian Charlotte Leser Jiansong Sheng Archana Jha Günter Vollmer Michael Schaefer Franz Bracher Christian Grimm
author_sort	Philipp Rühl
title	Estradiol analogs attenuate autophagy, cell migration and invasion by direct and selective inhibition of TRPML1, independent of estrogen receptors
title_short	Estradiol analogs attenuate autophagy, cell migration and invasion by direct and selective inhibition of TRPML1, independent of estrogen receptors
title_full	Estradiol analogs attenuate autophagy, cell migration and invasion by direct and selective inhibition of TRPML1, independent of estrogen receptors
title_fullStr	Estradiol analogs attenuate autophagy, cell migration and invasion by direct and selective inhibition of TRPML1, independent of estrogen receptors
title_full_unstemmed	Estradiol analogs attenuate autophagy, cell migration and invasion by direct and selective inhibition of TRPML1, independent of estrogen receptors
title_sort	estradiol analogs attenuate autophagy, cell migration and invasion by direct and selective inhibition of trpml1, independent of estrogen receptors
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/4ae8395bdd4d48a1b970609d440ac4a3
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_version_	1718391366073974784

Estradiol analogs attenuate autophagy, cell migration and invasion by direct and selective inhibition of TRPML1, independent of estrogen receptors

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