TitleTargeting the Hsp90-associated viral oncoproteome in gammaherpesvirus-associated malignancies.
Publication TypeJournal Article
Year of Publication2013
AuthorsNayar, Utthara, Lu Pin, Goldstein Rebecca L., Vider Jelena, Ballon Gianna, Rodina Anna, Taldone Tony, Erdjument-Bromage Hediye, Chomet Max, Blasberg Ronald, Melnick Ari, Cerchietti Leandro, Chiosis Gabriela, Y Wang Lynn, and Cesarman Ethel
Date Published2013 Oct 17
KeywordsAnimals, Apoptosis, Autophagy, Benzodioxoles, Cell Line, Tumor, Cell Proliferation, Gammaherpesvirinae, Herpesviridae Infections, HSP90 Heat-Shock Proteins, Humans, Mice, Neoplasm Transplantation, Neoplasms, NF-kappa B, Proteome, Proteomics, Purines, Signal Transduction, Viral Proteins

<p>PU-H71 is a purine-scaffold Hsp90 inhibitor that, in contrast to other Hsp90 inhibitors, displays unique selectivity for binding the fraction of Hsp90 that is preferentially associated with oncogenic client proteins and enriched in tumor cells (teHsp90). This property allows PU-H71 to potently suppress teHsp90 without inducing toxicity in normal cells. We found that lymphoma cells infected by Epstein-Barr virus or Kaposi sarcoma-associated herpes virus (KSHV) are exquisitely sensitive to this compound. Using PU-H71 affinity capture and proteomics, an unbiased approach to reveal oncogenic networks, we identified the teHsp90 interactome in KSHV(+) primary effusion lymphoma cells. Viral and cellular proteins were identified, including many involved in nuclear factor (NF)-κB signaling, apoptosis, and autophagy. KSHV vFLIP is a viral oncoprotein homologous to cFLIPs, with NF-κB-activating and antiapoptotic activities. We show that teHsp90 binds vFLIP but not cFLIPs. Treatment with PU-H71 induced degradation of vFLIP and IKKγ, NF-κB downregulation, apoptosis and autophagy in vitro, and more importantly, tumor responses in mice. Analysis of the interactome revealed apoptosis as a central pathway; therefore, we tested a BCL2 family inhibitor in primary effusion lymphoma cells. We found strong activity and synergy with PU-H71. Our findings demonstrate PU-H71 affinity capture identifies actionable networks that may help design rational combinations of effective therapies.</p>

Alternate JournalBlood
PubMed ID23943653
PubMed Central IDPMC3798998
Grant ListR01 CA103646 / CA / NCI NIH HHS / United States
R01 CA068939 / CA / NCI NIH HHS / United States
R01 CA155226 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R01 CA154228 / CA / NCI NIH HHS / United States
R01 CA172546 / CA / NCI NIH HHS / United States
UL1 TR000457 / TR / NCATS NIH HHS / United States
R21 CA158609 / CA / NCI NIH HHS / United States
T32 AI007621 / AI / NIAID NIH HHS / United States
R01-CA68939 / CA / NCI NIH HHS / United States
P30CA008748 / CA / NCI NIH HHS / United States