Reactivation of the p53 pathway as a treatment modality for KSHV-induced lymphomas

J Clin Invest. 2007 Apr;117(4):1019-28. doi: 10.1172/JCI30945. Epub 2007 Mar 15.


Kaposi's sarcoma herpesvirus (KSHV) is the etiologic agent for primary effusion lymphoma (PEL), a non-Hodgkin type lymphoma manifesting as an effusion malignancy in the affected individual. Although KSHV has been recognized as a tumor virus for over a decade, the pathways for its tumorigenic conversion are incompletely understood, which has greatly hampered the development of efficient therapies for KSHV-induced malignancies like PEL and Kaposi's sarcoma. There are no current therapies effective against the aggressive, KSHV-induced PEL. Here we demonstrate that activation of the p53 pathway using murine double minute 2 (MDM2) inhibitor Nutlin-3a conveyed specific and highly potent activation of PEL cell killing. Our results demonstrated that the KSHV latency-associated nuclear antigen (LANA) bound to both p53 and MDM2 and that the MDM2 inhibitor Nutlin-3a disrupted the p53-MDM2-LANA complex and selectively induced massive apoptosis in PEL cells. Together with our results indicating that KSHV-infection activated DNA damage signaling, these findings contribute to the specificity of the cytotoxic effects of Nutlin-3a in KSHV-infected cells. Moreover, we showed that Nutlin-3a had striking antitumor activity in vivo in a mouse xenograft model. Our results therefore present new options for exploiting reactivation of p53 as what we believe to be a novel and highly selective treatment modality for this virally induced lymphoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle / drug effects
  • Cell Survival / drug effects
  • DNA Damage
  • DNA, Neoplasm / drug effects
  • DNA, Neoplasm / genetics
  • Gene Expression Regulation, Neoplastic*
  • Genes, p53*
  • Herpesvirus 4, Human / pathogenicity
  • Herpesvirus 4, Human / physiology
  • Herpesvirus 8, Human / pathogenicity
  • Herpesvirus 8, Human / physiology*
  • Humans
  • Imidazoles / pharmacology
  • Lymphoma / genetics
  • Lymphoma / virology*
  • Mice
  • Piperazines / pharmacology
  • Sarcoma, Kaposi / genetics*
  • Sarcoma, Kaposi / virology
  • Transplantation, Heterologous
  • Tumor Suppressor Protein p53 / genetics*
  • Virus Latency


  • DNA, Neoplasm
  • Imidazoles
  • Piperazines
  • Tumor Suppressor Protein p53
  • nutlin 3