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

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 3

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Protein expression. (A) LANA levels of untreated and GA-treated cells. T...
Protein expression. (A) LANA levels of untreated and GA-treated cells. Tubulin and actin were used as controls. Lanes 1, 4, and 7: untreated cells; lanes 2, 5, and 8: cells treated with 3 mM GA; lanes 3, 6, and 9: cells treated with 4 mM GA. One representative experiment is shown. The SD from 3 independent experiments is 0.22. (B) FACS analysis of untreated and GA-treated cells stained with FITC-conjugated anti–v-cyclin. Because v-cyclin is constitutively expressed by all KSHV-infected cells, the graph shows the percentage of cells overexpressing v-cyclin. Values of GA-treated BCBL-1, BC-3, and BC-1 cells are relative to those of the same untreated cells, arbitrarily set to 1. Columns 1, 4, and 7: untreated cells; columns 2, 5, and 8: cells treated with 3 mM GA; columns 3, 6, and 9: cells treated with 4 mM GA. Values are the average of 3 experiments with 3 repeats per sample. Data represent the mean ± SEM. (C) FACS profiles of BC-3 and BC-1 cells, untreated and treated with GA and stained with FITC-conjugated anti–v-cyclin. BCBL-1 profiles were similar to those of BC-1 and BC-3 (not shown). One representative experiment is shown. (D) v-FLIP expression. Immunoblotting of cells untreated and treated with GA. Tubulin was used as control. Lane 1: BJAB cells (negative control); lanes 2, 5, and 8: untreated cells; lanes 3, 6, and 9: cells treated with 3 mM GA; lanes 4, 7, and 10: cells treated with 4 mM GA. One representative experiment is shown. (E) CDK6 expression. Immunoblotting of BC-1, BC-3, BCBL-1, BJAB, primary human lymphocytes (H-Lymph), primary human hepatocytes (H-Liver), and 293 cells. Lanes 1, 4, and 7: untreated cells; lanes 2, 5, and 8: cells treated with 3 mM GA; lanes 3, 6, and 9: cells treated with 4 mM GA. Tubulin was used as control. One representative experiment is shown. The SD from 3 independent experiments is ± 0.20.