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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1019-1028
Number of pages10
JournalJournal of Clinical Investigation
Volume117
Issue number4
DOIs
StatePublished - Apr 2 2007
Externally publishedYes

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Kaposi's Sarcoma
Herpesviridae
Primary Effusion Lymphoma
Lymphoma
Herpesviridae Infections
Oncogenic Viruses
Heterografts
Non-Hodgkin's Lymphoma
DNA Damage
Neoplasms
Apoptosis
nutlin 3
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Sarek, G., Kurki, S., Enbäck, J., Iotzova, G., Haas, J., Laakkonen, P., ... Ojala, P. M. (2007). Reactivation of the p53 pathway as a treatment modality for KSHV-induced lymphomas. Journal of Clinical Investigation, 117(4), 1019-1028. https://doi.org/10.1172/JCI30945

Reactivation of the p53 pathway as a treatment modality for KSHV-induced lymphomas. / Sarek, Grzegorz; Kurki, Sari; Enbäck, Juulia; Iotzova, Guergana; Haas, Juergen; Laakkonen, Pirjo; Laiho, Marikki; Ojala, Päivi M.

In: Journal of Clinical Investigation, Vol. 117, No. 4, 02.04.2007, p. 1019-1028.

Research output: Contribution to journalArticle

Sarek, G, Kurki, S, Enbäck, J, Iotzova, G, Haas, J, Laakkonen, P, Laiho, M & Ojala, PM 2007, 'Reactivation of the p53 pathway as a treatment modality for KSHV-induced lymphomas', Journal of Clinical Investigation, vol. 117, no. 4, pp. 1019-1028. https://doi.org/10.1172/JCI30945
Sarek G, Kurki S, Enbäck J, Iotzova G, Haas J, Laakkonen P et al. Reactivation of the p53 pathway as a treatment modality for KSHV-induced lymphomas. Journal of Clinical Investigation. 2007 Apr 2;117(4):1019-1028. https://doi.org/10.1172/JCI30945
Sarek, Grzegorz ; Kurki, Sari ; Enbäck, Juulia ; Iotzova, Guergana ; Haas, Juergen ; Laakkonen, Pirjo ; Laiho, Marikki ; Ojala, Päivi M. / Reactivation of the p53 pathway as a treatment modality for KSHV-induced lymphomas. In: Journal of Clinical Investigation. 2007 ; Vol. 117, No. 4. pp. 1019-1028.
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