Reactivation of the p53 pathway as a treatment modality for KSHV-induced lymphomas.
J Clin Invest
; 117(4): 1019-28, 2007 Apr.
Article
em En
| MEDLINE
| ID: mdl-17364023
ABSTRACT
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.
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Base de dados:
MEDLINE
Assunto principal:
Sarcoma de Kaposi
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Regulação Neoplásica da Expressão Gênica
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Genes p53
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Proteína Supressora de Tumor p53
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Herpesvirus Humano 8
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Linfoma
Idioma:
En
Ano de publicação:
2007
Tipo de documento:
Article