Abstract
APE1 is a multifunctional protein with a DNA base excision repair function in its C-terminal domain and a redox activity in its N-terminal domain. The redox function of APE1 converts certain transcription factors from inactive oxidized to active reduced forms. Given that among the APE1-regulated transcription factors many are critical for KSHV replication and pathogenesis, we investigated whether inhibition of APE1 redox function blocks KSHV replication and Kaposi’s sarcoma (KS) phenotypes. With an shRNA-mediated silencing approach and a known APE-1 redox inhibitor, we demonstrated that APE1 redox function is indeed required for KSHV replication as well as KSHV-induced angiogenesis, validating APE1 as a therapeutic target for KSHV-associated diseases. A ligand-based virtual screening yielded a small molecular compound, C10, which is proven to bind to APE1. C10 exhibits low cytotoxicity but efficiently inhibits KSHV lytic replication (EC50 of 0.16 μM and selective index of 165) and KSHV-mediated pathogenic phenotypes including cytokine production, angiogenesis and cell invasion, demonstrating its potential to become an effective drug for treatment of KS.
Highlights
Kaposi’s sarcoma-associated herpesvirus (KSHV), termed human herpesvirus type 8 (HHV8), is a member of the γ-herpesviridae subfamily
We showed that the redox function of apyrimidinic endonuclease 1 (APE1) is absolutely required for KSHV replication, virally induced cytokine secretion and angiogenesis
Blockade of APE1 expression or inhibition of APE1 redox activity led to inhibition of KSHV replication and reduction of cytokine release and angiogenesis
Summary
Kaposi’s sarcoma-associated herpesvirus (KSHV), termed human herpesvirus type 8 (HHV8), is a member of the γ-herpesviridae subfamily. This virus has been proven to be the etiological agent of Kaposi’s sarcoma (KS) [1]. Almost 100% of KS lesions, regardless of their source or clinic subtype (i.e., classic, AIDS-associated, African endemic, and post transplant KS), are infected with KSHV. KS is the most common malignancy associated with HIV-infection. KSHV is associated with two lymphoproliferative diseases, namely primary effusion lymphoma (PEL) [3] and multicentric Castleman’s disease (MCD) [4]. There is no definitive cure for KS and other KSHV-associate diseases
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
