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

Grzegorz Sarek, Sari Kurki, Juulia Enbäck, Guergana Iotzova, Juergen Haas, Pirjo Maarit Laakkonen, Marikki Laiho, Päivi Ojala

Research output: Contribution to journalArticleScientificpeer-review

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 Nutfn-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 Nutfn-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.
Original languageEnglish
JournalJournal of Clinical Investigation
Volume117
Issue number4
Pages (from-to)1019-1028
Number of pages10
ISSN0021-9738
DOIs
Publication statusPublished - 2007
MoE publication typeA1 Journal article-refereed

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