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

[primary effusion lymphoma]

PU-H 71 is a purine-scaffold Hsp 90 inhibitor that , in contrast to other Hsp 90 inhibitors , displays unique selectivity for binding the fraction of Hsp 90 that is preferentially associated with oncogenic client proteins and enriched in tumor cells (teHsp 90 ). This property allows PU-H 71 to potently suppress teHsp 90 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-H 71 affinity capture and proteomics , an unbiased approach to reveal oncogenic networks , we identified the teHsp 90 interactome in KSHV (+) primary effusion lymphoma cells . Viral and cellular proteins were identified , including many involved in nuclear factor (NF )-ÎºB signaling , apoptosis , and autophagy . KSHV vFLIP is a viral oncoprotein homologous to cFLIPs , with NF-ÎºB-activating and antiapoptotic activities . We show that teHsp 90 binds vFLIP but not cFLIPs . Treatment with PU-H 71 induced degradation of vFLIP and IKK Î³ , NF-ÎºB 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 BCL 2 family inhibitor in primary effusion lymphoma cells . We found strong activity and synergy with PU-H 71 . Our findings demonstrate PU-H 71 affinity capture identifies actionable networks that may help design rational combinations of effective therapies .

Diseases
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Diseases presenting "oncogenic client proteins" symptom

primary effusion lymphoma

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