Ribonucleotide reductase represents a novel therapeutic target in primary effusion lymphoma

• Published in: Oncogene Vol. 36; no. 35; pp. 5068 - 5074
• Main Authors: Dai, L, Lin, Z, Qiao, J, Chen, Y, Flemington, E K, Qin, Z
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 31-08-2017; Nature Publishing Group
• Subjects: 45; 45/61; 631/67/1059; 631/67/1990; 64/60; Animals; Apoptosis; Apoptosis - drug effects; c-Met protein; Cancer; Care and treatment; Cell Biology; Cell cycle; Cell Line, Tumor; Chemotherapy; Drug resistance; Effusion; Enzyme Inhibitors - pharmacology; Gene expression; Hepatocyte growth factor; Human Genetics; Humans; Immunodeficiency; Infections; Internal Medicine; Kaposi's sarcoma; Lymphocytes B; Lymphoma; Lymphoma, Primary Effusion - drug therapy; Lymphoma, Primary Effusion - enzymology; Lymphoma, Primary Effusion - genetics; Lymphoma, Primary Effusion - pathology; Lymphomas; Male; Malignancy; Medicine; Medicine & Public Health; Mice; Mice, Inbred NOD; Mice, SCID; Molecular Targeted Therapy; Oncology; Primary effusion lymphoma; Pyridines - pharmacology; Reductase; Ribonucleoside reductase; Ribonucleotide reductase; Ribonucleotide Reductases - antagonists & inhibitors; Ribonucleotide Reductases - metabolism; Rodents; short-communication; Signal Transduction; Therapeutic applications; Therapeutic targets; Thiosemicarbazones - pharmacology; Transcriptome - drug effects; Transcriptomes; Viruses; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2017.122

Primary effusion lymphoma (PEL) is a highly aggressive B-cell malignancy that is closely associated with one of oncogenic viruses infection, Kaposi’s sarcoma-associated herpesvirus. PEL prognosis is poor and patients barely survive >6 months even following active chemotherapy interventions. There is therefore an urgent need to discover more effective targets for PEL management. We recently found that the ribonucleotide reductase (RR) subunit M2 is potentially regulated by the key oncogenic hepatocyte growth factor/c-MET pathway in PEL. In this study, we set to investigate the role of RR in PEL pathogenesis and to evaluate its potential as a therapeutic target. We report that the RR inhibitor 3-AP actively induces PEL cell cycle arrest through inhibiting the activity of the nuclear factor-κB pathway. Using a xenograft model, we found that 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) effectively suppresses PEL progression in immunodeficient mice. Transcriptome analysis of 3-AP-treated PEL cell lines reveals altered cellular genes, most of whose roles in PEL have not yet been reported. Taken together, we propose that RR and its signaling pathway may serve as novel actionable targets for PEL management.