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Glycyrrhizic acid alters Kaposi sarcoma–associated herpesvirus latency, triggering p53-mediated apoptosis in transformed B lymphocytes
Francesca Curreli, … , Alvin E. Friedman-Kien, Ornella Flore
Francesca Curreli, … , Alvin E. Friedman-Kien, Ornella Flore
Published March 1, 2005
Citation Information: J Clin Invest. 2005;115(3):642-652. https://doi.org/10.1172/JCI23334.
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Article Virology Article has an altmetric score of 4

Glycyrrhizic acid alters Kaposi sarcoma–associated herpesvirus latency, triggering p53-mediated apoptosis in transformed B lymphocytes

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Abstract

Kaposi sarcoma–associated herpesvirus (KSHV) is linked with all clinical forms of Kaposi sarcoma and several lymphoproliferative disorders. Like other herpesviruses, KSHV becomes latent in the infected cells, expressing only a few genes that are essential for the establishment and maintenance of its latency and for the survival of the infected cells. Inhibiting the expression of these latent genes should lead to eradication of herpesvirus infection. All currently available drugs are ineffective against latent infection. Here we show, for the first time to our knowledge, that latent infection with KSHV in B lymphocytes can be terminated by glycyrrhizic acid (GA), a triterpenoid compound earlier shown to inhibit the lytic replication of other herpesviruses. We demonstrate that GA disrupts latent KSHV infection by downregulating the expression of latency-associated nuclear antigen (LANA) and upregulating the expression of viral cyclin and selectively induces cell death of KSHV-infected cells. We show that reduced levels of LANA lead to p53 reactivation, an increase in ROS, and mitochondrial dysfunction, which result in G1 cell cycle arrest, DNA fragmentation, and oxidative stress–mediated apoptosis. Latent genes are involved in KSHV-induced oncogenesis, and strategies to interfere with their expression might prove useful for eradicating latent KSHV infection and have future therapeutic implications.

Authors

Francesca Curreli, Alvin E. Friedman-Kien, Ornella Flore

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Figure 4

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Apoptosis signaling. (A) Analysis of mitochondrial membrane potential di...
Apoptosis signaling. (A) Analysis of mitochondrial membrane potential disruption in BJAB, BCBL-1, BC-3, and BC-1 cells untreated or treated for 4 days with 4 mM GA. In healthy cells, mitochondria appear red, as shown in untreated cells and in GA-treated BJAB cells. In dying cells with disrupted potential, the dye appears green, as shown in BCBL-1, BC-3, and BC-1 cells treated with GA. Valinomycin (100 nM) was used as positive control. (B) TUNEL assay to detect chromatin condensation in BJAB, BCBL-1, BC-3, and BC-1 cells after 4 days of treatment with 4 mM GA (green). Cells were counterstained with DAPI to localize the nuclei (blue). TPA was used as a negative control to show that lytic cycle induction does not promote chromatin condensation. Numbers indicate the percentage of TUNEL-positive cells in the same culture determined by flow cytometric analysis.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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