TY - JOUR
T1 - Targeting the Hsp90-associated viral oncoproteome in gammaherpesvirus-associated malignancies
AU - Nayar, Utthara
AU - Lu, Pin
AU - Goldstein, Rebecca L.
AU - Vider, Jelena
AU - Ballon, Gianna
AU - Rodina, Anna
AU - Taldone, Tony
AU - Erdjument-Bromage, Hediye
AU - Chomet, Max
AU - Blasberg, Ronald
AU - Melnick, Ari
AU - Cerchietti, Leandro
AU - Chiosis, Gabriela
AU - Wang, Y. Lynn
AU - Cesarman, Ethel
N1 - Funding Information:
This work was funded by grants from the National Institutes of Health/ National Cancer Institute (R01-CA68939) (E.C.), (P30CA008748) (E.C. and G.C.), (P30CA008748) (Microchemistry and Proteomics Core Laboratory of Memorial Sloan-Kettering Cancer Center), and T32 AI007621 Immunology and Microbial Pathogenesis Program Training Grant (U.N).
Publisher Copyright:
© 2013 by The American Society of Hematology.
PY - 2013
Y1 - 2013
N2 - 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)-kB signaling, apoptosis, and autophagy. KSHV vFLIP is a viral oncoprotein homologous to cFLIPs, with NF-kB–activating and antiapoptotic activities. We show that teHsp90 binds vFLIP but not cFLIPs. Treatment with PU-H71 induced degradation of vFLIP and IKKg, NF-kB 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.
AB - 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)-kB signaling, apoptosis, and autophagy. KSHV vFLIP is a viral oncoprotein homologous to cFLIPs, with NF-kB–activating and antiapoptotic activities. We show that teHsp90 binds vFLIP but not cFLIPs. Treatment with PU-H71 induced degradation of vFLIP and IKKg, NF-kB 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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U2 - 10.1182/blood-2013-01-479972
DO - 10.1182/blood-2013-01-479972
M3 - Article
C2 - 23943653
AN - SCOPUS:84887440198
SN - 0006-4971
VL - 122
SP - 2837
EP - 2847
JO - Blood
JF - Blood
IS - 16
ER -