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

Forskningsoutput: TidskriftsbidragArtikelVetenskapligPeer review

Sammanfattning

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.
Originalspråkengelska
TidskriftJournal of Clinical Investigation
Volym117
Utgåva4
Sidor (från-till)1019-1028
Antal sidor10
ISSN0021-9738
DOI
StatusPublicerad - 2007
MoE-publikationstypA1 Tidskriftsartikel-refererad

Citera det här

Sarek, Grzegorz ; Kurki, Sari ; Enbäck, Juulia ; Iotzova, Guergana ; Haas, Juergen ; Laakkonen, Pirjo Maarit ; Laiho, Marikki ; Ojala, Päivi. / Reactivation of the p53 pathway as a treatment modality for KSHV-induced lymphomas. I: Journal of Clinical Investigation. 2007 ; Vol. 117, Nr. 4. s. 1019-1028.
@article{4c540d5692c044dd9a36c00b070559a5,
title = "Reactivation of the p53 pathway as a treatment modality for KSHV-induced lymphomas",
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.",
author = "Grzegorz Sarek and Sari Kurki and Juulia Enb{\"a}ck and Guergana Iotzova and Juergen Haas and Laakkonen, {Pirjo Maarit} and Marikki Laiho and P{\"a}ivi Ojala",
year = "2007",
doi = "10.1172/JCI30945",
language = "English",
volume = "117",
pages = "1019--1028",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "AMERICAN SOCIETY FOR CLINICAL INVESTIGATION",
number = "4",

}

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 Maarit; Laiho, Marikki; Ojala, Päivi.

I: Journal of Clinical Investigation, Vol. 117, Nr. 4, 2007, s. 1019-1028.

Forskningsoutput: TidskriftsbidragArtikelVetenskapligPeer review

TY - JOUR

T1 - Reactivation of the p53 pathway as a treatment modality for KSHV-induced lymphomas

AU - Sarek, Grzegorz

AU - Kurki, Sari

AU - Enbäck, Juulia

AU - Iotzova, Guergana

AU - Haas, Juergen

AU - Laakkonen, Pirjo Maarit

AU - Laiho, Marikki

AU - Ojala, Päivi

PY - 2007

Y1 - 2007

N2 - 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.

AB - 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.

U2 - 10.1172/JCI30945

DO - 10.1172/JCI30945

M3 - Article

VL - 117

SP - 1019

EP - 1028

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 4

ER -