Reactivation of the p53 pathway as a treatment modality for KSHV-induced lymphomas.
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.
Sarek
Grzegorz
G
Genome-Scale Biology Program, Biomedicum Helsinki, Institute of Biomedicine, University of Helsinki, Helsinki, Finland.
Kurki
Sari
S
Enbäck
Juulia
J
Iotzova
Guergana
G
Haas
Juergen
J
Laakkonen
Pirjo
P
Laiho
Marikki
M
Ojala
Päivi M
PM
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D004854:Herpesvirus 4, Human / Q000472:pathogenicity / Q000502:physiology; D019288:Herpesvirus 8, Human / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008223:Lymphoma / Q000235:genetics / Q000821:virology*; D051379:Mice; D010879:Piperazines / Q000494:pharmacology; D012514:Sarcoma, Kaposi / Q000235:genetics* / Q000821:virology; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D017735:Virus Latency
D004273:DNA, Neoplasm; D007093:Imidazoles; D010879:Piperazines; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3