Journal article

Dysregulated fibronectin trafficking by Hsp90 inhibition restricts prostate cancer cell invasion

Heather K Armstrong, Joanna L Gillis, Ian RD 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

Scientific Reports | NATURE PUBLISHING GROUP | Published : 2018

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 ..

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University of Melbourne Researchers

Grants

Awarded by Cancer Australia


Awarded by Prostate Cancer Foundation of Australia through the Movember Revolutionary Team Awards


Awarded by Development Grant from the National Health and Medical Research Council of Australia (NHMRC)


Awarded by National Health and Medical Research Council (NHMRC)


Awarded by Prostate Cancer Foundation of Australia


Awarded by Future Fellowship from the Australian Research Council


Funding Acknowledgements

This study was supported by Cancer Australia (1050880 and 1085471 to L.M.B. and M.M.C.), the Movember Foundation and the Prostate Cancer Foundation of Australia through the Movember Revolutionary Team Awards 1 and 3 (L.M.B., M.M.C., M.C.S. and L.A.S.), a Development Grant from the National Health and Medical Research Council of Australia (NHMRC; 1092904 to D.A.B. and L.M.B.) and the Australian Government Department of Health (M.C.S. and C.L.). H.K.A. was supported by an Australian Postgraduate Award and the Freemason's Foundation Centre for Men's Health at the University of Adelaide, I.R.D.J. is supported by the Prostate Cancer Foundation of Australia, D.J.L. is supported by an EMBL Australia Group Leader Award, L.A.S. was supported by a Young Investigator Award from the Prostate Cancer Foundation (the Foundation 14 award) and a Project Grant from the National Health and Medical Research Council (NHMRC; APP1083961), M.M.C. was supported by a Young Investigator Award (ID 0412) from the Prostate Cancer Foundation of Australia, and L.M.B. is supported by a Future Fellowship from the Australian Research Council (FT130101004). The authors gratefully acknowledge Dr Jane Sottile (University of Rochester) for supplying the fibronectin antibody and inhibitory peptide pUR4, and Dr Nicole Moore for critical review of data.