WRN-targeted therapy using inhibitors NSC 19630 and NSC 617145 induce apoptosis in HTLV-1-transformed adult T-cell leukemia cells.
Human T-cell leukemia virus type 1 (HTLV-1) infection is associated with adult T-cell leukemia/lymphoma (ATLL), a lymphoproliferative malignancy with a dismal prognosis and limited therapeutic options. Recent evidence shows that HTLV-1-transformed cells present defects in both DNA replication and DNA repair, suggesting that these cells might be particularly sensitive to treatment with a small helicase inhibitor. Because the "Werner syndrome ATP-dependent helicase" encoded by the WRN gene plays important roles in both cellular proliferation and DNA repair, we hypothesized that inhibition of WRN activity could be used as a new strategy to target ATLL cells.



Our analysis demonstrates an apoptotic effect induced by the WRN helicase inhibitor in HTLV-1-transformed cells in vitro and ATL-derived cell lines. Inhibition of cellular proliferation and induction of apoptosis were demonstrated with cell cycle analysis, XTT proliferation assay, clonogenic assay, annexin V staining, and measurement of mitochondrial transmembrane potential.



Targeted inhibition of the WRN helicase induced cell cycle arrest and apoptosis in HTLV-1-transformed leukemia cells. Treatment with NSC 19630 (WRN inhibitor) induces S-phase cell cycle arrest, disruption of the mitochondrial membrane potential, and decreased expression of anti-apoptotic factor Bcl-2. These events were associated with activation of caspase-3-dependent apoptosis in ATL cells. We identified some ATL cells, ATL-55T and LMY1, less sensitive to NSC 19630 but sensitive to another WRN inhibitor, NSC 617145.



WRN is essential for survival of ATL cells. Our studies suggest that targeting the WRN helicase with small inhibitors is a novel promising strategy to target HTLV-1-transformed ATL cells.
Department of Pathology and Laboratory Medicine, Center for Viral Oncology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA.
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Moles
Department of Pathology and Laboratory Medicine, Center for Viral Oncology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA.
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Bai
Department of Pathology and Laboratory Medicine, Center for Viral Oncology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA.
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Chaib-Mezrag
Department of Pathology and Laboratory Medicine, Center for Viral Oncology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA. cnicot@kumc.edu.|Department of Pathology and Laboratory Medicine, Center for Viral Oncology, KU Cancer Center, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS, 66160, USA. cnicot@kumc.edu.
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D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy* / Q000473:pathology; D008301:Maleimides / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D000071657:Werner Syndrome Helicase / Q000037:antagonists & inhibitors* / Q000502:physiology
C557741:1-(propoxymethyl)maleimide; D004791:Enzyme Inhibitors; D008301:Maleimides; C584579:NSC 617145; D053148:Caspase 3; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase
Adult T-cell leukemia/lymphoma (ATLL); Apoptosis; Cycle arrest; Human T-cell leukemia virus type 1 (HTLV-1); WRN helicase