%0 Journal Article
%T Hypoxia-inducible factor-1 alpha as a therapeutic target for primary effusion lymphoma
%A Coralie Viollet
%A David A. Davis
%A Prabha Shrestha
%A Ravindra P. Veeranna
%A Robert F. Carey
%A Robert Yarchoan
%J -
%D 2017
%R 10.1371/journal.ppat.1006628
%X Primary effusion lymphoma (PEL) is an aggressive B-cell lymphoma with poor prognosis caused by Kaposi¡¯s sarcoma-associated herpesvirus (KSHV). Previous studies have revealed that HIF-1¦Á, which mediates much of the cellular response to hypoxia, plays an important role in life cycle of KSHV. KSHV infection promotes HIF-1¦Á activity, and several KSHV genes are in turn activated by HIF-1¦Á. In this study, we investigated the effects of knocking down HIF-1¦Á in PELs. We observed that HIF-1¦Á knockdown in each of two PEL lines leads to a reduction in both aerobic and anaerobic glycolysis as well as lipid biogenesis, indicating that HIF-1¦Á is necessary for maintaining a metabolic state optimal for growth of PEL. We also found that HIF-1¦Á suppression leads to a substantial reduction in activation of lytic KSHV genes, not only in hypoxia but also in normoxia. Moreover, HIF-1¦Á knockdown led to a decrease in the expression of various KSHV latent genes, including LANA, vCyclin, kaposin, and miRNAs, under both normoxic and hypoxic conditions. These observations provide evidence that HIF-1¦Á plays an important role in PEL even in normoxia. Consistent with these findings, we observed a significant inhibition of growth of PEL in normoxia upon HIF-1¦Á suppression achieved by either HIF-1¦Á knockdown or treatment with PX-478, a small molecule inhibitor of HIF-1¦Á. These results offer further evidence that HIF-1¦Á plays a critical role in the pathogenesis of PEL, and that inhibition of HIF-1¦Á can be a potential therapeutic strategy in this disease
%K Hypoxia
%K MicroRNAs
%K Glycolysis
%K Kaposi's sarcoma-associated herpesvirus
%K Gene expression
%K Lipids
%K Carcinogenesis
%K B cells
%U https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1006628