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

• Published in: PLoS pathogens 2017-09, Vol.13 (9), p.e1006628-e1006628
• Main Authors: Shrestha, Prabha, Davis, David A, Veeranna, Ravindra P, Carey, Robert F, Viollet, Coralie, Yarchoan, Robert
• Format: Article
• Language: English
• Subjects: Acquired immune deficiency syndrome; AIDS; Antigens, Viral - genetics; Antigens, Viral - immunology; B-cell lymphoma; Biology and Life Sciences; Cancer therapies; Care and treatment; Cell Hypoxia; Diagnosis; Effusion; Gene expression; Gene Expression Regulation, Viral - drug effects; Genes; Glycolysis; Herpes; Herpesvirus diseases; HIV; Human immunodeficiency virus; Humans; Hypoxia; Hypoxia-inducible factor 1; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-inducible factor 1a; Hypoxia-inducible factors; Inhibition; Kaposis sarcoma; Kinases; Life cycle engineering; Life cycles; Lymphocytes B; Lymphoma; Lymphoma, Primary Effusion - drug therapy; Lymphoma, Primary Effusion - virology; Medical prognosis; Medical research; Medicine and Health Sciences; Metabolism; MicroRNAs - metabolism; Mustard Compounds - pharmacology; Non-Hodgkin's lymphomas; Pathogenesis; Phenylpropionates - pharmacology; Phosphorylation; Primary effusion lymphoma; Prognosis; Proteins; Reduction; Sarcoma; Sarcoma, Kaposi - virology; Studies; Transcription activation; Tumors
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1006628

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.