title: Discovery of nonsteroidal anti-inflammatory drug and anticancer drug enhancing reprogramming and induced pluripotent stem cell generation.
abstract: Recent breakthroughs in creating induced pluripotent stem cells (iPSCs) provide alternative means to obtain embryonic stem-like cells without destroying embryos by introducing four reprogramming factors (Oct3/4, Sox2, and Klf4/c-Myc or Nanog/Lin28) into somatic cells. iPSCs are versatile tools for investigating early developmental processes and could become sources of tissues or cells for regenerative therapies. Here, for the first time, we describe a strategy to analyze genomics datasets of mouse embryonic fibroblasts (MEFs) and embryonic stem cells to identify genes constituting barriers to iPSC reprogramming. We further show that computational chemical biology combined with genomics analysis can be used to identify small molecules regulating reprogramming. Specific downregulation by small interfering RNAs (siRNAs) of several key MEF-specific genes encoding proteins with catalytic or regulatory functions, including WISP1, PRRX1, HMGA2, NFIX, PRKG2, COX2, and TGFβ3, greatly increased reprogramming efficiency. Based on this rationale, we screened only 17 small molecules in reprogramming assays and discovered that the nonsteroidal anti-inflammatory drug Nabumetone and the anticancer drug 4-hydroxytamoxifen can generate iPSCs without Sox2. Nabumetone could also produce iPSCs in the absence of c-Myc or Sox2 without compromising self-renewal and pluripotency of derived iPSCs. In summary, we report a new concept of combining genomics and computational chemical biology to identify new drugs useful for iPSC generation. This hypothesis-driven approach provides an alternative to shot-gun screening and accelerates understanding of molecular mechanisms underlying iPSC induction.
authors: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors: Chao-Shun
authors: CS
authors: Yang
authors: Claudia G
authors: CG
authors: Lopez
authors: Tariq M
authors: TM
authors: Rana
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002074:Butanones / Q000494:pharmacology; D055511:CCN Intercellular Signaling Proteins / Q000235:genetics / Q000378:metabolism; D019295:Computational Biology; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D055808:Drug Discovery; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D020868:Gene Silencing; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000187:drug effects; D000090062:Kruppel-Like Factor 4; D051379:Mice; D008819:Mice, Nude; D000077430:Nabumetone; D020411:Oligonucleotide Array Sequence Analysis; D011247:Pregnancy; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D013724:Teratoma / Q000378:metabolism / Q000473:pathology; D014162:Transfection; D053782:Transforming Growth Factor beta3 / Q000235:genetics / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D002074:Butanones; D055511:CCN Intercellular Signaling Proteins; C492067:CCN4 protein, mouse; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D053782:Transforming Growth Factor beta3; D013629:Tamoxifen; C016601:afimoxifene; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D000077430:Nabumetone