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Reactivation of the p53 pathway as a treatment modality for KSHV-induced lymphomas
Grzegorz Sarek, … , Marikki Laiho, Päivi M. Ojala
Grzegorz Sarek, … , Marikki Laiho, Päivi M. Ojala
Published April 2, 2007
Citation Information: J Clin Invest. 2007;117(4):1019-1028. https://doi.org/10.1172/JCI30945.
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Research Article Oncology Article has an altmetric score of 7

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

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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.

Authors

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

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Figure 6

Nutlin-3a disrupts the p53-MDM2-LANA interaction.

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Nutlin-3a disrupts the p53-MDM2-LANA interaction.
(A) Extracts from the ...
(A) Extracts from the BC-3 cell line exposed for 12 hours to vehicle control or 7 μM Nutlin-3a were separated using gel filtration chromatography. Fractions were analyzed by Western blotting with antibodies against p53, MDM2, and LANA. The elution profile of molecular weight standards is indicated above the lanes. (B) The peak fractions for LANA (asterisks in A) from BC-3 cells treated with either vehicle control or 7 μM Nutlin-3a for 12 hours were used in immunoprecipitations with anti-p53 or anti-MDM2 antibodies. As a control, a duplicate sample from the same fraction was immunoprecipitated with mouse IgG. Immunocomplexes were resolved by SDS-PAGE and analyzed by Western blotting with antibodies against p53, MDM2, and LANA.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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