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- Title
Hypoxia-inducible factor-1 alpha as a therapeutic target for primary effusion lymphoma.
- Authors
Shrestha, Prabha; Davis, David A.; Veeranna, Ravindra P.; Carey, Robert F.; Viollet, Coralie; Yarchoan, Robert
- Abstract
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-1α, which mediates much of the cellular response to hypoxia, plays an important role in life cycle of KSHV. KSHV infection promotes HIF-1α activity, and several KSHV genes are in turn activated by HIF-1α. In this study, we investigated the effects of knocking down HIF-1α in PELs. We observed that HIF-1α 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-1α is necessary for maintaining a metabolic state optimal for growth of PEL. We also found that HIF-1α suppression leads to a substantial reduction in activation of lytic KSHV genes, not only in hypoxia but also in normoxia. Moreover, HIF-1α 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-1α 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-1α suppression achieved by either HIF-1α knockdown or treatment with PX-478, a small molecule inhibitor of HIF-1α. These results offer further evidence that HIF-1α plays a critical role in the pathogenesis of PEL, and that inhibition of HIF-1α can be a potential therapeutic strategy in this disease.
- Subjects
LYMPHOMAS; KAPOSI'S sarcoma-associated herpesvirus diseases; HYPOXEMIA; GLYCOLYSIS; MICRORNA; PROGNOSIS
- Publication
PLoS Pathogens, 2017, Vol 13, Issue 9, p1
- ISSN
1553-7366
- Publication type
Article
- DOI
10.1371/journal.ppat.1006628