Abstract
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.
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References
Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, Knowles DM et al. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science 1994; 266: 1865–1869.
Cesarman E, Chang Y, Moore PS, Said JW, Knowles DM . Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. N Engl J Med 1995; 332: 1186–1191.
Chen YB, Rahemtullah A, Hochberg E . Primary effusion lymphoma. Oncologist 2007; 12: 569–576.
Simonelli C, Spina M, Cinelli R, Talamini R, Tedeschi R, Gloghini A et al. Clinical features and outcome of primary effusion lymphoma in HIV-infected patients: a single-institution study. J Clin Oncol 2003; 21: 3948–3954.
Boulanger E, Gerard L, Gabarre J, Molina JM, Rapp C, Abino JF et al. Prognostic factors and outcome of human herpesvirus 8-associated primary effusion lymphoma in patients with AIDS. J Clin Oncol 2005; 23: 4372–4380.
Qin Z, Dai L, Bratoeva M, Slomiany MG, Toole BP, Parsons C . Cooperative roles for emmprin and LYVE-1 in the regulation of chemoresistance for primary effusion lymphoma. Leukemia 2011; 25: 1598–1609.
Flepisi BT, Bouic P, Sissolak G, Rosenkranz B . Drug-drug interactions in HIV positive cancer patients. Biomed Pharmacother 2014; 68: 665–677.
Dai L, Trillo-Tinoco J, Cao Y, Bonstaff K, Doyle L, Del Valle L et al. Targeting HGF/c-MET induces cell cycle arrest, DNA damage, and apoptosis for primary effusion lymphoma. Blood 2015; 126: 2821–2831.
Zhou B, Su L, Hu S, Hu W, Yip ML, Wu J et al. A small-molecule blocking ribonucleotide reductase holoenzyme formation inhibits cancer cell growth and overcomes drug resistance. Cancer Res 2013; 73: 6484–6493.
Larsson A, Stenberg K, Ericson AC, Haglund U, Yisak WA, Johansson NG et al. Mode of action, toxicity, pharmacokinetics, and efficacy of some new antiherpesvirus guanosine analogs related to buciclovir. Antimicrob Agents Chemother 1986; 30: 598–605.
Fan H, Villegas C, Huang A, Wright JA . The mammalian ribonucleotide reductase R2 component cooperates with a variety of oncogenes in mechanisms of cellular transformation. Cancer Res 1998; 58: 1650–1653.
Fan H, Huang A, Villegas C, Wright JA . The R1 component of mammalian ribonucleotide reductase has malignancy-suppressing activity as demonstrated by gene transfer experiments. Proc Natl Acad Sci USA 1997; 94: 13181–13186.
Iwaki T, Iwaki A, Fukumaki Y, Tateishi J . Alpha B-crystallin in C6 glioma cells supports their survival in elevated extracellular K+: the implication of a protective role of alpha B-crystallin accumulation in reactive glia. Brain Res 1995; 673: 47–52.
Liu SQ, Saijo K, Todoroki T, Ohno T . Induction of human autologous cytotoxic T lymphocytes on formalin-fixed and paraffin-embedded tumour sections. Nat Med 1995; 1: 267–271.
Georgakilas AG, Martin OA, Bonner WM . p21: a two-faced genome guardian. Trends Mol Med 2017; 23: 310–319 pii: S1471-4914(17)30020-5.
Sarek G, Ma L, Enback J, Jarviluoma A, Moreau P, Haas J et al. Kaposi's sarcoma herpesvirus lytic replication compromises apoptotic response to p53 reactivation in virus-induced lymphomas. Oncogene 2013; 32: 1091–1098.
Chen W, Hilton IB, Staudt MR, Burd CE, Dittmer DP Distinct p53, p53:LANA, and LANA complexes in Kaposi's sarcoma-associated herpesvirus lymphomasJ Virol 2010; 84: 3898–3908.
Gottwein E, Cullen BR . A human herpesvirus microRNA inhibits p21 expression and attenuates p21-mediated cell cycle arrest. J Virol 2010; 84: 5229–5237.
Qin Z, Dai L, Trillo-Tinoco J, Senkal C, Wang W, Reske T et al. Targeting sphingosine kinase induces apoptosis and tumor regression for KSHV-associated primary effusion lymphoma. Mol Cancer Ther 2014; 13: 154–164.
Defee MR, Qin Z, Dai L, Toole BP, Isaacs JS, Parsons CH . Extracellular Hsp90 serves as a co-factor for NF-kappaB activation and cellular pathogenesis induced by an oncogenic herpesvirus. Am J Cancer Res 2011; 1: 687–700.
Dai L, Trillo-Tinoco J, Bai L, Kang B, Xu Z, Wen X et al. Systematic analysis of a xenograft mice model for KSHV+ primary effusion lymphoma (PEL). PLoS One 2014; 9: e90349.
Sasai K, Treekitkarnmongkol W, Kai K, Katayama H, Sen S . Functional significance of aurora kinases-p53 protein family interactions in cancer. Front Oncol 2016; 6: 247.
Falchook GS, Bastida CC, Kurzrock R . Aurora kinase inhibitors in oncology clinical trials: current state of the progress. Semin Oncol 2015; 42: 832–848.
Toole BP . Hyaluronan: from extracellular glue to pericellular cue. Nat Rev Cancer 2004; 4: 528–539.
Nyholm S, Thelander L, Graslund A . Reduction and loss of the iron center in the reaction of the small subunit of mouse ribonucleotide reductase with hydroxyurea. Biochemistry 1993; 32: 11569–11574.
Yen Y, Margolin K, Doroshow J, Fishman M, Johnson B, Clairmont C et al. A phase I trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone in combination with gemcitabine for patients with advanced cancer. Cancer Chemother Pharmacol 2004; 54: 331–342.
Stadler WM, Desai AA, Quinn DI, Bukowski R, Poiesz B, Kardinal CG et al. A phase I/II study of GTI-2040 and capecitabine in patients with renal cell carcinoma. Cancer Chemother Pharmacol 2008; 61: 689–694.
Shao J, Zhou B, Zhu L, Bilio AJ, Su L, Yuan YC et al. Determination of the potency and subunit-selectivity of ribonucleotide reductase inhibitors with a recombinant-holoenzyme-based in vitro assay. Biochem Pharmacol 2005; 69: 627–634.
Weinberg ED . The role of iron in cancer. Eur J Cancer Prev 1996; 5: 19–36.
Cazzola M, Bergamaschi G, Dezza L, Arosio P . Manipulations of cellular iron metabolism for modulating normal and malignant cell proliferation: achievements and prospects. Blood 1990; 75: 1903–1919.
Simonart T . Iron: a target for the management of Kaposi's sarcoma? BMC Cancer 2004; 4: 1.
Simonart T, Degraef C, Andrei G, Mosselmans R, Hermans P, Van Vooren JP et al. Iron chelators inhibit the growth and induce the apoptosis of Kaposi's sarcoma cells and of their putative endothelial precursors. J Invest Dermatol 2000; 115: 893–900.
Dai L, Trillo-Tinoco J, Chen Y, Bonstaff K, Del Valle L, Parsons C et al. CD147 and downstream ADAMTSs promote the tumorigenicity of Kaposi's sarcoma-associated herpesvirus infected endothelial cells. Oncotarget 2016; 7: 3806–3818.
Acknowledgements
This work was partially supported by grants from a DOD Career Development Award (CA140437), the Leukemia Research Foundation, the Louisiana Clinical and Translational Science Center Pilot grants (U54GM104940 from NIH), NIH RO1s (AI101046 and AI106676), as well as awards from the National Natural Science Foundation of China (81472547, 81672924 and 81400164). Funding sources had no role in the study design, data collection/analysis, decision to publish and/or manuscript preparation.
Author contributions
LD and ZQ designed and performed experiments, analyzed results, wrote the manuscript, and ZQ is the corresponding author. ZL and JQ performed experiments. ZL, YC and EKF performed statistical analysis or provided critical input.
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Dai, L., Lin, Z., Qiao, J. et al. Ribonucleotide reductase represents a novel therapeutic target in primary effusion lymphoma. Oncogene 36, 5068–5074 (2017). https://doi.org/10.1038/onc.2017.122
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DOI: https://doi.org/10.1038/onc.2017.122
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