Therapeutically actionable signaling node to rescue AURKA driven loss of primary cilia in VHL-deficient cells

Abstract Loss of primary cilia in cells deficient for the tumor suppressor von Hippel Lindau (VHL) arise from elevated Aurora Kinase A (AURKA) levels. VHL in its role as an E3 ubiquitin ligase targets AURKA for degradation and in the absence of VHL, high levels of AURKA result in destabilization of...

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Autores principales: Pratim Chowdhury, Dimuthu Perera, Reid T. Powell, Tia Talley, Durga Nand Tripathi, Yong Sung Park, Michael A. Mancini, Peter Davies, Clifford Stephan, Cristian Corfa, Ruhee Dere
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Publicado: Nature Portfolio 2021
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Acceso en línea:https://doaj.org/article/2ca73e95c5024ae6a9c8ae5e0e85611a
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spelling oai:doaj.org-article:2ca73e95c5024ae6a9c8ae5e0e85611a2021-12-02T15:45:21ZTherapeutically actionable signaling node to rescue AURKA driven loss of primary cilia in VHL-deficient cells10.1038/s41598-021-89933-72045-2322https://doaj.org/article/2ca73e95c5024ae6a9c8ae5e0e85611a2021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-89933-7https://doaj.org/toc/2045-2322Abstract Loss of primary cilia in cells deficient for the tumor suppressor von Hippel Lindau (VHL) arise from elevated Aurora Kinase A (AURKA) levels. VHL in its role as an E3 ubiquitin ligase targets AURKA for degradation and in the absence of VHL, high levels of AURKA result in destabilization of the primary cilium. We identified NVP-BEZ235, a dual PI3K/AKT and mTOR inhibitor, in an image-based high throughput screen, as a small molecule that restored primary cilia in VHL-deficient cells. We identified the ability of AKT to modulate AURKA expression at the transcript and protein level. Independent modulation of AKT and mTOR signaling decreased AURKA expression in cells confirming AURKA as a new signaling node downstream of the PI3K cascade. Corroborating these data, a genetic knockdown of AKT in cells deficient for VHL rescued the ability of these cells to ciliate. Finally, inhibition of AKT/mTOR using NVP-BEZ235 was efficacious in reducing tumor burden in a 786-0 xenograft model of renal cell carcinoma. These data highlight a previously unappreciated signaling node downstream of the AKT/mTOR pathway via AURKA that can be targeted in VHL-null cells to restore ciliogenesis.Pratim ChowdhuryDimuthu PereraReid T. PowellTia TalleyDurga Nand TripathiYong Sung ParkMichael A. ManciniPeter DaviesClifford StephanCristian CorfaRuhee DereNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Pratim Chowdhury
Dimuthu Perera
Reid T. Powell
Tia Talley
Durga Nand Tripathi
Yong Sung Park
Michael A. Mancini
Peter Davies
Clifford Stephan
Cristian Corfa
Ruhee Dere
Therapeutically actionable signaling node to rescue AURKA driven loss of primary cilia in VHL-deficient cells
description Abstract Loss of primary cilia in cells deficient for the tumor suppressor von Hippel Lindau (VHL) arise from elevated Aurora Kinase A (AURKA) levels. VHL in its role as an E3 ubiquitin ligase targets AURKA for degradation and in the absence of VHL, high levels of AURKA result in destabilization of the primary cilium. We identified NVP-BEZ235, a dual PI3K/AKT and mTOR inhibitor, in an image-based high throughput screen, as a small molecule that restored primary cilia in VHL-deficient cells. We identified the ability of AKT to modulate AURKA expression at the transcript and protein level. Independent modulation of AKT and mTOR signaling decreased AURKA expression in cells confirming AURKA as a new signaling node downstream of the PI3K cascade. Corroborating these data, a genetic knockdown of AKT in cells deficient for VHL rescued the ability of these cells to ciliate. Finally, inhibition of AKT/mTOR using NVP-BEZ235 was efficacious in reducing tumor burden in a 786-0 xenograft model of renal cell carcinoma. These data highlight a previously unappreciated signaling node downstream of the AKT/mTOR pathway via AURKA that can be targeted in VHL-null cells to restore ciliogenesis.
format article
author Pratim Chowdhury
Dimuthu Perera
Reid T. Powell
Tia Talley
Durga Nand Tripathi
Yong Sung Park
Michael A. Mancini
Peter Davies
Clifford Stephan
Cristian Corfa
Ruhee Dere
author_facet Pratim Chowdhury
Dimuthu Perera
Reid T. Powell
Tia Talley
Durga Nand Tripathi
Yong Sung Park
Michael A. Mancini
Peter Davies
Clifford Stephan
Cristian Corfa
Ruhee Dere
author_sort Pratim Chowdhury
title Therapeutically actionable signaling node to rescue AURKA driven loss of primary cilia in VHL-deficient cells
title_short Therapeutically actionable signaling node to rescue AURKA driven loss of primary cilia in VHL-deficient cells
title_full Therapeutically actionable signaling node to rescue AURKA driven loss of primary cilia in VHL-deficient cells
title_fullStr Therapeutically actionable signaling node to rescue AURKA driven loss of primary cilia in VHL-deficient cells
title_full_unstemmed Therapeutically actionable signaling node to rescue AURKA driven loss of primary cilia in VHL-deficient cells
title_sort therapeutically actionable signaling node to rescue aurka driven loss of primary cilia in vhl-deficient cells
publisher Nature Portfolio
publishDate 2021
url https://doaj.org/article/2ca73e95c5024ae6a9c8ae5e0e85611a
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