Glycyrrhizic acid alters Kaposi sarcoma-associated herpesvirus latency, triggering p53-mediated apoptosis in transformed B lymphocytes.
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.
Curreli
Francesca
F
Department of Microbiology, New York University School of Medicine, New York, New York 10016, USA.
Friedman-Kien
Alvin E
AE
Flore
Ornella
O
D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001402:B-Lymphocytes / Q000187:drug effects* / Q000502:physiology / Q000821:virology; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D019695:Glycyrrhizic Acid / Q000494:pharmacology* / Q000627:therapeutic use; D006566:Herpesviridae Infections / Q000188:drug therapy / Q000378:metabolism; D019288:Herpesvirus 8, Human / Q000187:drug effects*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation; D015398:Signal Transduction / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D017735:Virus Latency / Q000187:drug effects*
D000890:Anti-Infective Agents; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D061945:Caspase Inhibitors; D016213:Cyclins; D047908:Intracellular Signaling Peptides and Proteins; D016159:Tumor Suppressor Protein p53; D014764:Viral Proteins; D019695:Glycyrrhizic Acid; D020169:Caspases