title: 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.
abstract: 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 EC(50) 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.
authors.affiliation: Department of Microbiology and Immunology, Program in Global Oncology, Lineberger Comprehensive Cancer Center, Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Wuguo
authors.initials: W
authors.lastname: Chen
authors.forename: Sang-Hoon
authors.initials: SH
authors.lastname: Sin
authors.forename: Kwun Wah
authors.initials: KW
authors.lastname: Wen
authors.forename: Blossom
authors.initials: B
authors.lastname: Damania
authors.forename: Dirk P
authors.initials: DP
authors.lastname: Dittmer
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D019288:Herpesvirus 8, Human / Q000502:physiology*; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis / Q000187:drug effects; D036104:Receptor, EphA2 / Q000235:genetics / Q000378:metabolism*; D012514:Sarcoma, Kaposi / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous; D017735:Virus Latency / Q000187:drug effects / Q000502:physiology
chemical_list: D000956:Antigens, Viral; D018841:HSP90 Heat-Shock Proteins; D009687:Nuclear Proteins; C109540:latency-associated nuclear antigen; D036104:Receptor, EphA2