Abstract
Kaposi sarcoma (KS) tumors often contain a wild-type p53. However, the function of this tumor suppressor in KS tumor cells is inhibited by both MDM2 and latent nuclear antigen (LANA) of Kaposi sarcoma-associated herpes virus (KSHV). Here, we report that MDM2 antagonist Nutlin-3 efficiently reactivates p53 in telomerase-immortalized human umbilical vein endothelial cells (TIVE) that had been malignantly transformed by KSHV as well as in KS tumor cells. Reactivation of p53 results in a G 1 cell cycle arrest, leading to inhibition of proliferation and apoptosis. Nutlin-3 inhibits the growth of "KS-like" tumors resulting from xenografted TIVE-KSHV cells in nude mice. In addition, Nutlin-3 strongly inhibits expression of the pro-angiogenic and pro-inflammatory cytokine angiopoietin-2 (Ang-2). It also disrupts viral latency by inducing expression of KSHV lytic genes. These results suggest that Nutlin-3 might serve as a novel therapy for KS.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Angiopoietin-2 / biosynthesis*
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Animals
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Apoptosis / drug effects*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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G1 Phase Cell Cycle Checkpoints / drug effects
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Herpesvirus 8, Human / physiology*
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Human Umbilical Vein Endothelial Cells / drug effects
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Human Umbilical Vein Endothelial Cells / metabolism
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Humans
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Imidazoles / pharmacology*
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Mice
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Mice, Nude
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Piperazines / pharmacology*
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Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors
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Proto-Oncogene Proteins c-mdm2 / metabolism
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Sarcoma, Kaposi / metabolism*
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Sarcoma, Kaposi / pathology
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Sarcoma, Kaposi / virology*
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Telomerase / metabolism
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism
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Virus Latency / drug effects*
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Xenograft Model Antitumor Assays
Substances
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Angiopoietin-2
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Imidazoles
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Piperazines
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Tumor Suppressor Protein p53
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nutlin 3
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2
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Telomerase