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dc.contributor.authorArmstrong, HK
dc.contributor.authorGillis, JL
dc.contributor.authorJohnson, IRD
dc.contributor.authorNassar, ZD
dc.contributor.authorMoldovan, M
dc.contributor.authorLevrier, C
dc.contributor.authorSadowski, MC
dc.contributor.authorChin, MY
dc.contributor.authorGuns, EST
dc.contributor.authorTarulli, G
dc.contributor.authorLynn, DJ
dc.contributor.authorBrooks, DA
dc.contributor.authorSelth, LA
dc.contributor.authorCentenera, MM
dc.contributor.authorButler, LM
dc.date.accessioned2020-12-09T23:56:22Z
dc.date.available2020-12-09T23:56:22Z
dc.date.issued2018-02-01
dc.identifierpii: 10.1038/s41598-018-19871-4
dc.identifier.citationArmstrong, H. K., Gillis, J. L., Johnson, I. R. D., Nassar, Z. D., Moldovan, M., Levrier, C., Sadowski, M. C., Chin, M. Y., Guns, E. S. T., Tarulli, G., Lynn, D. J., Brooks, D. A., Selth, L. A., Centenera, M. M. & Butler, L. M. (2018). Dysregulated fibronectin trafficking by Hsp90 inhibition restricts prostate cancer cell invasion. SCIENTIFIC REPORTS, 8 (1), https://doi.org/10.1038/s41598-018-19871-4.
dc.identifier.issn2045-2322
dc.identifier.urihttp://hdl.handle.net/11343/253368
dc.description.abstractThe 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.
dc.languageEnglish
dc.publisherNATURE PUBLISHING GROUP
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titleDysregulated fibronectin trafficking by Hsp90 inhibition restricts prostate cancer cell invasion
dc.typeJournal Article
dc.identifier.doi10.1038/s41598-018-19871-4
melbourne.affiliation.departmentSchool of BioSciences
melbourne.source.titleScientific Reports
melbourne.source.volume8
melbourne.source.issue1
dc.rights.licenseCC BY
melbourne.elementsid1312386
melbourne.contributor.authorTarulli, Gerard
dc.identifier.eissn2045-2322
melbourne.accessrightsOpen Access


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