Combined inhibition of heat shock proteins 90 and 70 leads to simultaneous degradation of the oncogenic signaling proteins involved in muscle invasive bladder cancer

Alice Cavanaugh; Brendon Juengst; Kathleen Sheridan; John F. Danella; Heinric Williams

doi:10.18632/oncotarget.5496

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Research Papers:

Combined inhibition of heat shock proteins 90 and 70 leads to simultaneous degradation of the oncogenic signaling proteins involved in muscle invasive bladder cancer

Alice Cavanaugh _, Brendon Juengst, Kathleen Sheridan, John F. Danella and Heinric Williams

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Oncotarget. 2015; 6:39821-39838. https://doi.org/10.18632/oncotarget.5496

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Abstract

Alice Cavanaugh1, Brendon Juengst2, Kathleen Sheridan1, John F. Danella3, Heinric Williams1,3

1Weis Center for Research, Geisinger Health System, Danville, PA, USA

2Penn State University, Department of Plant Biology, State College, PA, USA

3Department of Urology, Geisinger Health System, Danville, PA, USA

Correspondence to:

Heinric Williams, e-mail: [email protected]

Keywords: heat shock protein 90, heat shock protein 70, muscle invasive bladder cancer

Received: June 26, 2015 Accepted: October 22, 2015 Published: November 04, 2015

ABSTRACT

Heat shock protein 90 (HSP90) plays a critical role in the survival of cancer cells including muscle invasive bladder cancer (MIBC). The addiction of tumor cells to HSP90 has promoted the development of numerous HSP90 inhibitors and their use in clinical trials. This study evaluated the role of inhibiting HSP90 using STA9090 (STA) alone or in combination with the HSP70 inhibitor VER155008 (VER) in several human MIBC cell lines. While both STA and VER inhibited MIBC cell growth and migration and promoted apoptosis, combination therapy was more effective. Therefore, the signaling pathways involved in MIBC were systematically interrogated following STA and/or VER treatments. STA and not VER reduced the expression of proteins in the p53/Rb, PI3K and SWI/SWF pathways. Interestingly, STA was not as effective as VER or combination therapy in degrading proteins involved in the histone modification pathway such as KDM6A (demethylase) and EP300 (acetyltransferase) as predicted by The Cancer Genome Atlas (TCGA) data. This data suggests that dual HSP90 and HSP70 inhibition can simultaneously disrupt the key signaling pathways in MIBC.

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Research Papers:

Combined inhibition of heat shock proteins 90 and 70 leads to simultaneous degradation of the oncogenic signaling proteins involved in muscle invasive bladder cancer

Abstract