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

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Faculté des Sciences Médicales et Paramédicales, Institut de Neurophysiopathologie (INP), Team 9, UMR 7051, CNRS, Aix Marseille Université, 13005 Marseille, France
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Faculté des Sciences Médicales et Paramédicales, Institut de Neurophysiopathologie (INP), Team 8, UMR 7051, CNRS, Aix Marseille Université, 13005 Marseille, France
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Service d’Anatomie Pathologique et de Neuropathologie, CHU Timone, APHM, 13005 Marseille, France
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LIM 64: Instituto do Coracao (InCor), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 05403-090, SP, Brazil
*
Author to whom correspondence should be addressed.
Academic Editors: Frank A.E. Kruyt, François Devred and Christian Poüs
Cancers 2021, 13(22), 5818; https://doi.org/10.3390/cancers13225818
Received: 30 September 2021 / Revised: 5 November 2021 / Accepted: 9 November 2021 / Published: 19 November 2021
(This article belongs to the Special Issue Microtubule-Associated Proteins (MAPs) and Cancers)
The Microtubule-associated protein Tau is expressed in different cancers; however, its role and prognostic value are still debated. In the present work, we evaluated the role of Tau in glioblastoma by down-regulating its expression in glioblastoma cells. We showed that Tau: (1) is required for tumor progression in nude mice; (2) is necessary for glioblastoma 3D cell organization, growth, and migration; and (3) regulates the PI3K/AKT signaling pathway.
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 MAPT 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. View Full-Text
Keywords: Microtubule-Associated Protein Tau (MAPT); glioblastoma; N-cadherin; PI3 kinase (PI3K); Akt; multicellular spheroid Microtubule-Associated Protein Tau (MAPT); glioblastoma; N-cadherin; PI3 kinase (PI3K); Akt; multicellular spheroid
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MDPI and ACS Style

Pagano, A.; Breuzard, G.; Parat, F.; Tchoghandjian, A.; Figarella-Branger, D.; De Bessa, T.C.; Garrouste, F.; Douence, A.; Barbier, P.; Kovacic, H. Tau Regulates Glioblastoma Progression, 3D Cell Organization, Growth and Migration via the PI3K-AKT Axis. Cancers 2021, 13, 5818. https://doi.org/10.3390/cancers13225818

AMA Style

Pagano A, Breuzard G, Parat F, Tchoghandjian A, Figarella-Branger D, De Bessa TC, Garrouste F, Douence A, Barbier P, Kovacic H. Tau Regulates Glioblastoma Progression, 3D Cell Organization, Growth and Migration via the PI3K-AKT Axis. Cancers. 2021; 13(22):5818. https://doi.org/10.3390/cancers13225818

Chicago/Turabian Style

Pagano, Alessandra, Gilles Breuzard, Fabrice Parat, Aurélie Tchoghandjian, Dominique Figarella-Branger, Tiphany C. De Bessa, Françoise Garrouste, Alexis Douence, Pascale Barbier, and Hervé Kovacic. 2021. "Tau Regulates Glioblastoma Progression, 3D Cell Organization, Growth and Migration via the PI3K-AKT Axis" Cancers 13, no. 22: 5818. https://doi.org/10.3390/cancers13225818

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