Universität zu Köln

Smithline, Zachary B., Nikonova, Anna S., Hensley, Harvey H., Cai, Kathy Q., Egleston, Brian L. ORCID: 0000-0002-1633-799X, Proia, David A., Seeger-Nukpezah, Tamina and Golemis, Erica A. (2014). Inhibiting Heat Shock Protein 90 (HSP90) Limits the Formation of Liver Cysts Induced by Conditional Deletion of Pkd1 in Mice. PLoS One, 9 (12). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1932-6203

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Smithline, Zachary B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Nikonova, Anna S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hensley, Harvey H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Cai, Kathy Q. UNSPECIFIED UNSPECIFIED UNSPECIFIED Egleston, Brian L. UNSPECIFIED orcid.org/0000-0002-1633-799X UNSPECIFIED Proia, David A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Seeger-Nukpezah, Tamina UNSPECIFIED UNSPECIFIED UNSPECIFIED Golemis, Erica A. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-420910
DOI:	10.1371/journal.pone.0114403
Journal or Publication Title:	PLoS One
Volume:	9
Number:	12
Date:	2014
Publisher:	PUBLIC LIBRARY SCIENCE
Place of Publication:	SAN FRANCISCO
ISSN:	1932-6203
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language POLYCYSTIC KIDNEY-DISEASE; AUTOSOMAL-DOMINANT; GROWTH; GANETESPIB; EVEROLIMUS; MODEL Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/42091