Tau Regulates Glioblastoma Progression, 3D Cell Organization, Growth and Migration via the PI3K-AKT Axis

The Microtubule-Associated Protein Tau is expressed in several cancers, including low-grade gliomas and glioblastomas. We have previously shown that Tau is crucial for the 2D motility of several glioblastoma cell lines, including U87-MG cells. Using an RNA interference (shRNA), we tested if Tau cont...

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Autores principales:	Alessandra Pagano, Gilles Breuzard, Fabrice Parat, Aurélie Tchoghandjian, Dominique Figarella-Branger, Tiphany Coralie De Bessa, Françoise Garrouste, Alexis Douence, Pascale Barbier, Hervé Kovacic
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	Microtubule-Associated Protein Tau (MAPT) glioblastoma N-cadherin PI3 kinase (PI3K) Akt multicellular spheroid Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/d1ee2278df8c4deeb69fd6b8526bc7af
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spelling	oai:doaj.org-article:d1ee2278df8c4deeb69fd6b8526bc7af2021-11-25T17:04:24ZTau Regulates Glioblastoma Progression, 3D Cell Organization, Growth and Migration via the PI3K-AKT Axis10.3390/cancers132258182072-6694https://doaj.org/article/d1ee2278df8c4deeb69fd6b8526bc7af2021-11-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/22/5818https://doaj.org/toc/2072-6694The Microtubule-Associated Protein Tau is expressed in several cancers, including low-grade gliomas and glioblastomas. We have previously shown that Tau is crucial for the 2D motility of several glioblastoma cell lines, including U87-MG cells. Using an RNA interference (shRNA), we tested if Tau contributed to glioblastoma in vivo tumorigenicity and analyzed its function in a 3D model of multicellular spheroids (MCS). Tau depletion significantly increased median mouse survival in an orthotopic glioblastoma xenograft model. This was accompanied by the inhibition of MCS growth and cell evasion, as well as decreased MCS compactness, implying N-cadherin mislocalization. Intracellular Signaling Array analysis revealed a defective activation of the PI3K/AKT pathway in Tau-depleted cells. Such a defect in PI3K/AKT signaling was responsible for reduced MCS growth and cell evasion, as demonstrated by the inhibition of the pathway in control MCS using LY294002 or Perifosine, which did not significantly affect Tau-depleted MCS. Finally, analysis of the glioblastoma TCGA dataset showed a positive correlation between the amount of phosphorylated Akt-Ser473 and the expression of <i>MAPT</i> RNA encoding Tau, underlining the relevance of our findings in glioblastoma disease. We suggest a role for Tau in glioblastoma by controlling 3D cell organization and functions via the PI3K/AKT signaling axis.Alessandra PaganoGilles BreuzardFabrice ParatAurélie TchoghandjianDominique Figarella-BrangerTiphany Coralie De BessaFrançoise GarrousteAlexis DouencePascale BarbierHervé KovacicMDPI AGarticleMicrotubule-Associated Protein Tau (MAPT)glioblastomaN-cadherinPI3 kinase (PI3K)Aktmulticellular spheroidNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5818, p 5818 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microtubule-Associated Protein Tau (MAPT) glioblastoma N-cadherin PI3 kinase (PI3K) Akt multicellular spheroid Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Microtubule-Associated Protein Tau (MAPT) glioblastoma N-cadherin PI3 kinase (PI3K) Akt multicellular spheroid Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Alessandra Pagano Gilles Breuzard Fabrice Parat Aurélie Tchoghandjian Dominique Figarella-Branger Tiphany Coralie De Bessa Françoise Garrouste Alexis Douence Pascale Barbier Hervé Kovacic Tau Regulates Glioblastoma Progression, 3D Cell Organization, Growth and Migration via the PI3K-AKT Axis
description	The Microtubule-Associated Protein Tau is expressed in several cancers, including low-grade gliomas and glioblastomas. We have previously shown that Tau is crucial for the 2D motility of several glioblastoma cell lines, including U87-MG cells. Using an RNA interference (shRNA), we tested if Tau contributed to glioblastoma in vivo tumorigenicity and analyzed its function in a 3D model of multicellular spheroids (MCS). Tau depletion significantly increased median mouse survival in an orthotopic glioblastoma xenograft model. This was accompanied by the inhibition of MCS growth and cell evasion, as well as decreased MCS compactness, implying N-cadherin mislocalization. Intracellular Signaling Array analysis revealed a defective activation of the PI3K/AKT pathway in Tau-depleted cells. Such a defect in PI3K/AKT signaling was responsible for reduced MCS growth and cell evasion, as demonstrated by the inhibition of the pathway in control MCS using LY294002 or Perifosine, which did not significantly affect Tau-depleted MCS. Finally, analysis of the glioblastoma TCGA dataset showed a positive correlation between the amount of phosphorylated Akt-Ser473 and the expression of <i>MAPT</i> RNA encoding Tau, underlining the relevance of our findings in glioblastoma disease. We suggest a role for Tau in glioblastoma by controlling 3D cell organization and functions via the PI3K/AKT signaling axis.
format	article
author	Alessandra Pagano Gilles Breuzard Fabrice Parat Aurélie Tchoghandjian Dominique Figarella-Branger Tiphany Coralie De Bessa Françoise Garrouste Alexis Douence Pascale Barbier Hervé Kovacic
author_facet	Alessandra Pagano Gilles Breuzard Fabrice Parat Aurélie Tchoghandjian Dominique Figarella-Branger Tiphany Coralie De Bessa Françoise Garrouste Alexis Douence Pascale Barbier Hervé Kovacic
author_sort	Alessandra Pagano
title	Tau Regulates Glioblastoma Progression, 3D Cell Organization, Growth and Migration via the PI3K-AKT Axis
title_short	Tau Regulates Glioblastoma Progression, 3D Cell Organization, Growth and Migration via the PI3K-AKT Axis
title_full	Tau Regulates Glioblastoma Progression, 3D Cell Organization, Growth and Migration via the PI3K-AKT Axis
title_fullStr	Tau Regulates Glioblastoma Progression, 3D Cell Organization, Growth and Migration via the PI3K-AKT Axis
title_full_unstemmed	Tau Regulates Glioblastoma Progression, 3D Cell Organization, Growth and Migration via the PI3K-AKT Axis
title_sort	tau regulates glioblastoma progression, 3d cell organization, growth and migration via the pi3k-akt axis
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/d1ee2278df8c4deeb69fd6b8526bc7af
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Tau Regulates Glioblastoma Progression, 3D Cell Organization, Growth and Migration via the PI3K-AKT Axis

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