Hsp90 inhibitors are efficacious against Kaposi Sarcoma by enhancing the degradation of the essential viral gene LANA, of the viral co-receptor EphA2 as well as other client proteins.

Wuguo Chen,Sang-Hoon Sin,Kwun Wah Wen,Blossom Damania,Dirk P Dittmer

doi:10.1371/journal.ppat.1003048

Wuguo Chen, Sang-Hoon Sin + Show 3 more

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Journal: PLoS Pathogens	Publication Date: Nov 29, 2012
Citations: 58	License type: CC BY 4.0

Affiliation: University of North Carolina at Chapel Hill, Bipar

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Heat-shock protein 90 (Hsp90) inhibitors exhibit activity against human cancers. We evaluated a series of new, oral bioavailable, chemically diverse Hsp90 inhibitors (PU-H71, AUY922, BIIB021, NVP-BEP800) against Kaposi sarcoma (KS). All Hsp90 inhibitors exhibited nanomolar EC50 in culture and AUY922 reduced tumor burden in a xenograft model of KS. KS is associated with KS-associated herpesvirus (KSHV). We identified the viral latency associated nuclear antigen (LANA) as a novel client protein of Hsp90 and demonstrate that the Hsp90 inhibitors diminish the level of LANA through proteasomal degradation. These Hsp90 inhibitors also downregulated EphA2 and ephrin-B2 protein levels. LANA is essential for viral maintenance and EphA2 has recently been shown to facilitate KSHV infection; which in turn feeds latent persistence. Further, both molecules are required for KS tumor formation and both were downregulated in response to Hsp90 inhibitors. This provides a rationale for clinical testing of Hsp90 inhibitors in KSHV-associated cancers and in the eradication of latent KSHV reservoirs.

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Heat shock protein 90 (Hsp90) is a conserved molecular chaperone that facilitates the maturation of a wide range of proteins and assists in the correct folding and productive assembly of cellular proteins and multimeric protein complexes in normally growing cells [1,2]
We focused our attention on (i) ephrins and ephrin receptors because of their connection to Kaposi sarcoma (KS) and Kaposi sarcoma associated herpesvirus (KSHV) infection and (ii) on the Kaposi sarcoma-associated herpesvirus (KSHV) latency associated nuclear antigen (LANA), which is essential for maintaining the KSHV virus and thereby the transformed phenotype [17]
Hsp90 interacts with KSHV LANA LANA is essential for maintaining latent KSHV, which is a prerequisite for PEL and KS tumorigenesis

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Heat shock protein 90 (Hsp90) is a conserved molecular chaperone that facilitates the maturation of a wide range of proteins and assists in the correct folding and productive assembly of cellular proteins and multimeric protein complexes in normally growing cells [1,2]. Hsp has important roles in maintaining the transformed phenotype of cancer cells. Cancer cells are critically addicted to the Hsp chaperone machinery whose activity protects an array of mutated and overexpressed oncoproteins, and other cellular client proteins from misfolding and degradation [7,8]. The newer class of Hsp inhibitors bind to the ATP-binding motif of Hsp and inhibit its protein chaperoning activity, resulting in misfolding, subsequent degradation of cellular client proteins, and tumor cell death [4,7,11,12]. Hsp inhibitors are selective for tumor cells because the chaperoning function of Hsp is required for most tumor cells. Even though the new inhibitors are highly selective for Hsp, Hsp has many client proteins, each of which can contribute to the transformed phenotype. Soluble extracellular Hsp has been implicated in supporting de novo infection by KSHV [16]

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