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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 3

Nutlin-3a has cytotoxic activity in PEL cells.

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Nutlin-3a has cytotoxic activity in PEL cells.
(A) PEL cell lines (BC-1,...
(A) PEL cell lines (BC-1, BC-3, and BCBL-1) and KSHV-infected LCL IHH (green symbols), EBV-transformed LCLs (CZE and IHE; blue symbols), or mutant p53 cells (DG-75 and HL-60; red symbols) were cultured for 5 days with 7 μM Nutlin-3a. Cell viability was determined by trypan blue exclusion at the indicated time points. Results are shown as survival curves denoting percentage of viable cells relative to the vehicle control. Data represent the mean of 3 independent experiments. (B) Scatter plot of annexin V–FITC/PI flow cytometry of BC-1 cells after exposure to 7 μM of Nutlin-3a or vehicle control for different time periods. (C) Apoptosis in BC-3, BCBL-1, CZE, IHE, DG-75, and HL-60 cells was assessed at 96 hours after treatment with 7 μM Nutlin-3a or vehicle control by annexin V–FITC/PI binding and measured by flow cytometry analysis. Lower left quadrants represent viable cells (annexin V– and PI-negative); lower right quadrants represent early apoptotic cells (annexin V–positive, PI-negative) demonstrating cytoplasmic membrane integrity; upper right quadrants represent nonviable, late apoptotic cells (annexin V– and PI-positive). Numbers indicate the percentage of cells in each quadrant. Shown is 1 representative experiment of 3.

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

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