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Inhibiting Heat Shock Protein 90 (HSP90) Limits the Formation of Liver Cysts Induced by Conditional Deletion of Pkd1 in Mice

Smithline, Zachary B.
; 
Nikonova, Anna S.
; ; 
Cai, Kathy Q.
; ; 
Proia, David A.
; 
Seeger-Nukpezah, Tamina
; 
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Journal article
Date
2014-12-04
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Committee member
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Fox Chase Cancer Center (Temple University)
Department
Cancer and Cellular Biology
Subject
Heat shock response
 Magnetic resonance imaging
 Drug therapy
 Kidneys
 Genetically modified animals
 Hematoxylin staining
 Liver and spleen scan
 Body weight
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http://hdl.handle.net/20.500.12613/9210
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GolemisEtAl-JournalArticle-2014-12.pdf
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http://dx.doi.org/10.1371/journal.pone.0114403
Abstract
Polycystic liver disease (PLD) occurs in 75–90% of patients affected by autosomal dominant polycystic kidney disease (ADPKD), which affects 1∶400–1,000 adults and arises from inherited mutations in the PKD1 or PKD2 genes. PLD can lead to bile duct obstructions, infected or bleeding cysts, and hepatomegaly, which can diminish quality of life. At present, no effective, approved therapy exists for ADPKD or PLD. We recently showed that inhibition of the molecular chaperone heat shock protein 90 (HSP90) with a small molecule inhibitor, STA-2842, induced the degradation of multiple HSP90-dependent client proteins that contribute to ADPKD pathogenesis and slowed the progression of renal cystogenesis in mice with conditional deletion of Pkd1. Here, we analyzed the effects of STA-2842 on liver size and cystic burden in Pkd-/- mice with established PLD. Using magnetic resonance imaging over time, we demonstrate that ten weeks of STA-2842 treatment significantly reduced both liver mass and cystic index suggesting selective elimination of cystic tissue. Pre-treatment cystic epithelia contain abundant HSP90; the degree of reduction in cysts was accompanied by inhibition of proliferation-associated signaling proteins EGFR and others, and induced cleavage of caspase 8 and PARP1, and correlated with degree of HSP90 inhibition and with inactivation of ERK1/2. Our results suggest that HSP90 inhibition is worth further evaluation as a therapeutic approach for patients with PLD.
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Smithline ZB, Nikonova AS, Hensley HH, Cai KQ, Egleston BL, Proia DA, Seeger-Nukpezah T, Golemis EA. Inhibiting Heat Shock Protein 90 (HSP90) Limits the Formation of Liver Cysts Induced by Conditional Deletion of Pkd1 in Mice. PLoS ONE. 2014 Jul 23;9(12):e114403. doi:10.1371/journal.pone.0114403.
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Public Library of Science
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PLoS One, Vol. 9
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