Hypoxia-inducible factor-1 alpha as a therapeutic target for primary effusion lymphoma

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 alpha, which mediates much of the cellular response to hypoxia, plays an important role in life cycle of KSHV. KSHV infection promotes HIF-1 alpha activity, and several KSHV genes are in turn activated by HIF-1 alpha. In this study, we investigated the effects of knocking down HIF-1 alpha in PELs. We observed that HIF-1 alpha 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 alpha is necessary for maintaining a metabolic state optimal for growth of PEL. We also found that HIF-1 alpha suppression leads to a substantial reduction in activation of lytic KSHV genes, not only in hypoxia but also in normoxia. Moreover, HIF-1 alpha 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 alpha 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 alpha suppression achieved by either HIF-1 alpha knockdown or treatment with PX-478, a small molecule inhibitor of HIF-1 alpha. These results offer further evidence that HIF-1 alpha plays a critical role in the pathogenesis of PEL, and that inhibition of HIF-1 alpha can be a potential therapeutic strategy in this disease.