Oncotarget

Research Papers:

Dual targeting of HSP70 does not induce the heat shock response and synergistically reduces cell viability in muscle invasive bladder cancer

Thomas Prince _, Andrew Ackerman, Alice Cavanaugh, Brielle Schreiter, Brendon Juengst, Chaylen Andolino, John Danella, Mitch Chernin and Heinric Williams

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Oncotarget. 2018; 9:32702-32717. https://doi.org/10.18632/oncotarget.26021

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Abstract

Thomas Prince1,2,*, Andrew Ackerman2,*, Alice Cavanaugh2, Brielle Schreiter1, Brendon Juengst2, Chaylen Andolino3, John Danella1, Mitch Chernin3 and Heinric Williams1,2

1Urology Department, Geisinger Clinic, Danville, 17822 PA, USA

2Weis Center for Research, Geisinger Clinic, Danville, 17822 PA, USA

3Biology Department, Bucknell University, Lewisburg, 17837 PA, USA

*These authors contributed equally to this work

Correspondence to:

Thomas Prince, email: tprince@geisinger.edu

Heinric Williams, email: hwilliams1@geisinger.edu

Keywords: HSP70; HSP90; bladder cancer; drug combination; synergy

Received: May 15, 2018     Accepted: August 13, 2018     Published: August 24, 2018

ABSTRACT

Muscle invasive bladder cancer (MIBC) is a common malignancy and major cause of morbidity worldwide. Over the last decade mortality rates for MIBC have not decreased as compared to other cancers indicating a need for novel strategies. The molecular chaperones HSP70 and HSP90 fold and maintain the 3-dimensional structures of numerous client proteins that signal for cancer cell growth and survival. Inhibition of HSP70 or HSP90 results in client protein degradation and associated oncogenic signaling. Here we targeted HSP70 and HSP90 with small molecule inhibitors that trap or block each chaperone in a low client-affinity “open” conformation. HSP70 inhibitors, VER155008 (VER) and MAL3-101 (MAL), along with HSP90 inhibitor, STA-9090 (STA), were tested alone and in combination for their ability to reduce cell viability and alter protein levels in 4 MIBC cell lines. When combined, VER+MAL synergistically reduced cell viability in each MIBC cell line while not inducing expression of heat shock proteins (HSPs). STA+MAL also synergistically reduced cell viability in each cell line but induced expression of cytoprotective HSPs indicating the merits of targeting HSP70 with VER+MAL. Additionally, we observed that STA induced the expression of the stress-related transcription factor HSF2 while reducing levels of the co-chaperone TTI1.


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