title: Lasonolide A, a potent and reversible inducer of chromosome condensation.
abstract: Lasonolide A (LSA) is a natural product with high and selective cytotoxicity against mesenchymal cancer cells, including leukemia, melanomas and glioblastomas. Here, we reveal that LSA induces rapid and reversible premature chromosome condensation (PCC) associated with cell detachment, plasma membrane smoothening and actin reorganization. PCC is induced at all phases of the cell cycle in proliferative cells as well as in circulating human lymphocytes in G 0. It is independent of Cdk1 signaling, associated with cyclin B downregulation and induced in cells at LSA concentrations that are three orders of magnitude lower than those required to block phosphatases 1 and 2A in vitro. At the epigenetic level, LSA-induced PCC is coupled with histone H3 and H1 hyperphosphorylation and deacetylation. Treatment with SAHA reduced LSA-induced PCC, implicating histone deacetylation as one of the PCC effector mechanisms. In addition, PCC is coupled with topoisomerase II (Top2) and Aurora A hyperphosphorylation and activation. Inhibition of Top2 or Aurora A partially blocked LSA-induced PCC. Our findings demonstrate the profound epigenetic alterations induced by LSA and the potential of LSA as a new cytogenetic tool. Based on the unique cellular effects of LSA, further studies are warranted to uncover the cellular target of lasonolide A ("TOL").
authors.affiliation: Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institute of Health, Bethesda, MD USA.
authors.forename: Yong-Wei
authors.initials: YW
authors.lastname: Zhang
authors.forename: Arun K
authors.initials: AK
authors.lastname: Ghosh
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
mesh_terms: D064127:Aurora Kinases; D016203:CDC2 Protein Kinase / Q000378:metabolism; D045744:Cell Line, Tumor; D002877:Chromosomes, Human / Q000187:drug effects* / Q000648:ultrastructure; D019926:Cyclin B / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology; D018942:Macrolides / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016192:Resting Phase, Cell Cycle
chemical_list: D019926:Cyclin B; D006657:Histones; D018942:Macrolides; C450700:lasonolide A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; D004250:DNA Topoisomerases, Type II