title: Sphingosine kinase-2 maintains viral latency and survival for KSHV-infected endothelial cells.
abstract: Phosphorylation of sphingosine by sphingosine kinases (SphK1 and SphK2) generates sphingosine-1-phosphate (S1P), a bioactive sphingolipid which promotes cancer cell survival and tumor progression in vivo. We have recently reported that targeting SphK2 induces apoptosis for human primary effusion lymphoma (PEL) cell lines infected by the Kaposi's sarcoma-associated herpesvirus (KSHV), and this occurs in part through inhibition of canonical NF-κB activation. In contrast, pharmacologic inhibition of SphK2 has minimal impact for uninfected B-cell lines or circulating human B cells from healthy donors. Therefore, we designed additional studies employing primary human endothelial cells to explore mechanisms responsible for the selective death observed for KSHV-infected cells during SphK2 targeting. Using RNA interference and a clinically relevant pharmacologic approach, we have found that targeting SphK2 induces apoptosis selectively for KSHV-infected endothelial cells through induction of viral lytic gene expression. Moreover, this effect occurs through repression of KSHV-microRNAs regulating viral latency and signal transduction, including miR-K12-1 which targets IκBα to facilitate activation of NF-κB, and ectopic expression of miR-K12-1 restores NF-κB activation and viability for KSHV-infected endothelial cells during SphK2 inhibition. These data illuminate a novel survival mechanism and potential therapeutic target for KSHV-infected endothelial cells: SphK2-associated maintenance of viral latency.
authors.affiliation: Research Center for Translational Medicine and Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai, China; Department of Medicine, Louisiana State University Health Sciences Center, HIV Malignancies Program, Louisiana Cancer Research Center, New Orleans, Louisiana, United States of America.
authors.forename: Lu
authors.initials: L
authors.lastname: Dai
authors.affiliation: Department of Medicine, Louisiana State University Health Sciences Center, HIV Malignancies Program, Louisiana Cancer Research Center, New Orleans, Louisiana, United States of America.
authors.forename: Karlie
authors.initials: K
authors.lastname: Plaisance-Bonstaff
authors.affiliation: Departments of Microbiology/Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Christina
authors.initials: C
authors.lastname: Voelkel-Johnson
authors.affiliation: Department of Drug Discovery/Biomedical Sciences, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Charles D
authors.initials: CD
authors.lastname: Smith
authors.affiliation: Department of Biochemistry/Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Besim
authors.initials: B
authors.lastname: Ogretmen
authors.affiliation: Research Center for Translational Medicine and Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai, China; Department of Microbiology/Immunology/Parasitology, Louisiana State University Health Sciences Center, HIV Malignancies Program, Louisiana Cancer Research Center, New Orleans, Louisiana, United States of America.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Qin
authors.affiliation: Department of Medicine, Louisiana State University Health Sciences Center, HIV Malignancies Program, Louisiana Cancer Research Center, New Orleans, Louisiana, United States of America; Department of Microbiology/Immunology/Parasitology, Louisiana State University Health Sciences Center, HIV Malignancies Program, Louisiana Cancer Research Center, New Orleans, Louisiana, United States of America.
authors.forename: Chris
authors.initials: C
authors.lastname: Parsons
mesh_terms: D017209:Apoptosis / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism / Q000821:virology; D015967:Gene Expression Regulation, Viral / Q000235:genetics; D019288:Herpesvirus 8, Human / Q000235:genetics* / Q000472:pathogenicity; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics* / Q000378:metabolism; D061251:Primary Cell Culture; D034622:RNA Interference; D017735:Virus Latency / Q000235:genetics*; D000099157:Sphingosine Kinase
chemical_list: D035683:MicroRNAs; D017853:Phosphotransferases (Alcohol Group Acceptor); C000594250:sphingosine kinase 2, human; D000099157:Sphingosine Kinase