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  • Targeting the Hsp90-associated viral oncoproteome in gammaherpesvirus-associated malignancies

    Author(s)
    Nayar, 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
    Wang, Y Lynn
    Cesarman, Ethel
    Griffith University Author(s)
    Vider, Jelena
    Year published
    2013
    Metadata
    Show full item record
    Abstract
    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 ...
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    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)-?B signaling, apoptosis, and autophagy. KSHV vFLIP is a viral oncoprotein homologous to cFLIPs, with NF-?B-activating and antiapoptotic activities. We show that teHsp90 binds vFLIP but not cFLIPs. Treatment with PU-H71 induced degradation of vFLIP and IKK?, NF-?B 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.
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    Journal Title
    Blood
    Volume
    122
    Issue
    16
    DOI
    https://doi.org/10.1182/blood-2013-01-479972
    Copyright Statement
    Self-archiving of the author-manuscript version is not yet supported by this journal. Please refer to the journal link for access to the definitive, published version or contact the author[s] for more information.
    Subject
    Cardiovascular medicine and haematology
    Clinical sciences
    Cancer cell biology
    Publication URI
    http://hdl.handle.net/10072/56396
    Collection
    • Journal articles

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