title: A Systematic Analysis of Negative Growth Control Implicates the DREAM Complex in Cancer Cell Dormancy.
abstract: Epithelial ovarian cancer (EOC) generates multicellular aggregates called spheroids that detach from the primary tumor and disseminate through ascites. Spheroids possess a number of characteristics of tumor dormancy including withdrawal from the cell cycle and resistance to chemotherapeutics. This report systematically analyzes the effects of RNAi depletion of 21 genes that are known to contribute to negative regulation of the cell cycle in 10 ovarian cancer cell lines. Interestingly, spheroid cell viability was compromised by loss of some cyclin-dependent kinase inhibitors such as p57Kip2, as well as Dyrk1A, Lin52, and E2F5 in most cell lines tested. Many genes essential for EOC spheroid viability are pertinent to the mammalian DREAM repressor complex. Mechanistically, the data demonstrate that DREAM is assembled upon the induction of spheroid formation, which is dependent upon Dyrk1A. Loss of Dyrk1A results in retention of the b-Myb-MuvB complex, elevated expression of DREAM target genes, and increased DNA synthesis that is coincident with cell death. Inhibition of Dyrk1A activity using pharmacologic agents Harmine and INDY compromises viability of spheroids and blocks DREAM assembly. In addition, INDY treatment improves the response to carboplatin, suggesting this is a therapeutic target for EOC treatment.Implications:Loss of negative growth control mechanisms in cancer dormancy lead to cell death and not proliferation, suggesting they are an attractive therapeutic approach.Mol Cancer Res; 15(4); 371-81. ©2016 AACR.
authors.affiliation: London Regional Cancer Program, London, Ontario, Canada.|Department of Biochemistry, Western University, London, Ontario, Canada.
authors.forename: James
authors.initials: J
authors.lastname: MacDonald
authors.affiliation: London Regional Cancer Program, London, Ontario, Canada.
authors.forename: Yudith
authors.initials: Y
authors.lastname: Ramos-Valdes
authors.affiliation: London Regional Cancer Program, London, Ontario, Canada.|Department of Biochemistry, Western University, London, Ontario, Canada.
authors.forename: Pirunthan
authors.initials: P
authors.lastname: Perampalam
authors.affiliation: Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Larissa
authors.initials: L
authors.lastname: Litovchick
authors.affiliation: London Regional Cancer Program, London, Ontario, Canada.|Department of Biochemistry, Western University, London, Ontario, Canada.|Department of Oncology, Western University, London, Ontario, Canada.
authors.forename: Gabriel E
authors.initials: GE
authors.lastname: DiMattia
authors.affiliation: London Regional Cancer Program, London, Ontario, Canada. fdick@uwo.ca.|Department of Biochemistry, Western University, London, Ontario, Canada.|Children's Health Research Institute, London, Ontario, Canada.
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Dick
mesh_terms: D016190:Carboplatin / Q000494:pharmacology; D000077216:Carcinoma, Ovarian Epithelial; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D006247:Harmine / Q000494:pharmacology; D006801:Humans; D051605:Kv Channel-Interacting Proteins / Q000235:genetics* / Q000378:metabolism; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D018874:Spheroids, Cellular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000097603:Dyrk Kinases
chemical_list: D016190:Carboplatin; D018797:Cell Cycle Proteins; D006247:Harmine; D051605:Kv Channel-Interacting Proteins; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D012097:Repressor Proteins; D015534:Trans-Activators; D000097603:Dyrk Kinases; C496749:KCNIP3 protein, human; C064352:MYBL2 protein, human