Role for the Werner syndrome protein in the promotion of tumor cell growth.
Werner syndrome (WS) is a premature aging and cancer-prone disease caused by loss of the RecQ helicase WRN protein. Cultured WS fibroblasts display high genomic instability and senesce prematurely. Epigenetic inactivation of the WRN gene occurs in numerous tumor types, in which WRN demonstrates tumor suppressor-like activity (Agrelo et al., 2006). However, the role of WRN in tumors that express WRN protein is unknown. Here we report that the inhibition of WRN expression strongly impairs growth of 12 out of 15 cancer cell lines tested. For those cell lines in which WRN depletion induced high cell death, the majority of the surviving proliferative clones exhibited WRN expression. Growth arrest induced by WRN depletion was characterized by an accumulation of cells in the G2/M cell cycle phases and an increase in DNA damage. Importantly, WRN depletion inhibited tumor growth in vivo in SCID mouse xenograft models. Altogether, these findings support a dual role for WRN in tumorigenesis; tumor suppressor-like activity in tumors with WRN inactivation and the promotion of proliferation and survival in tumors that express WRN. These findings suggest a possible therapeutic role for WRN as an anti-cancer target, and highlight the importance of WRN protein status for tumorigenesis and clinical treatments of patients.
Opresko
Patricia L
PL
University of Pittsburgh, Department of Environmental and Occupational Health, Pittsburgh, PA, USA. plo4@pitt.edu
Calvo
José Palacios
JP
von Kobbe
Cayetano
C
D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology / Q000503:physiopathology*; D002455:Cell Division / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D016922:Cellular Senescence / Q000502:physiology*; D005090:Exodeoxyribonucleases; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D007668:Kidney / Q000166:cytology; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000473:pathology / Q000503:physiopathology*; D034741:RNA, Small Interfering; D053484:RecQ Helicases / Q000235:genetics* / Q000378:metabolism; D014898:Werner Syndrome / Q000473:pathology* / Q000503:physiopathology*; D000071657:Werner Syndrome Helicase
D034741:RNA, Small Interfering; D005090:Exodeoxyribonucleases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase