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Type: Journal article
Title: Dysregulated fibronectin trafficking by Hsp90 inhibition restricts prostate cancer cell invasion
Author: Armstrong, H.
Gillis, J.
Johnson, I.
Nassar, Z.
Moldovan, M.
Levrier, C.
Sadowski, M.
Chin, M.
Tomlinson Guns, E.
Tarulli, G.
Lynn, D.
Brooks, D.
Selth, L.
Centenera, M.
Butler, L.
Citation: Scientific Reports, 2018; 8(1):2090-1-2090-14
Issue Date: 2018
ISSN: 2045-2322
Statement of
Heather K. Armstrong, Joanna L. Gillis, Ian R.D. Johnson, Zeyad D. Nassar, Max Moldovan, Claire Levrier, Martin C. Sadowski, Mei Yieng Chin, Emma S. Tomlinson Guns, Gerard Tarulli, David J. Lynn, Douglas A. Brooks, Luke A. Selth, Margaret M. Centenera, Lisa M. Butler
Abstract: The molecular chaperone Hsp90 is overexpressed in prostate cancer (PCa) and is responsible for the folding, stabilization and maturation of multiple oncoproteins, which are implicated in PCa progression. Compared to first-in-class Hsp90 inhibitors such as 17-allylamino-demethoxygeldanamycin (17-AAG) that were clinically ineffective, second generation inhibitor AUY922 has greater solubility and efficacy. Here, transcriptomic and proteomic analyses of patient-derived PCa explants identified cytoskeletal organization as highly enriched with AUY922 treatment. Validation in PCa cell lines revealed that AUY922 caused marked alterations to cell morphology, and suppressed cell motility and invasion compared to vehicle or 17-AAG, concomitant with dysregulation of key extracellular matrix proteins such as fibronectin (FN1). Interestingly, while the expression of FN1 was increased by AUY922, FN1 secretion was significantly decreased. This resulted in cytosolic accumulation of FN1 protein within late endosomes, suggesting that AUY922 disrupts vesicular secretory trafficking pathways. Depletion of FN1 by siRNA knockdown markedly reduced the invasive capacity of PCa cells, phenocopying AUY922. These results highlight a novel mechanism of action for AUY922 beyond its established effects on cellular mitosis and survival and, furthermore, identifies extracellular matrix cargo delivery as a potential therapeutic target for the treatment of aggressive PCa.
Keywords: Membrane trafficking; prostate cancer; proteomics; RNAi; transcriptomics
Rights: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit © The Author(s) 2018
DOI: 10.1038/s41598-018-19871-4
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