title: Obtusilactone B from Machilus Thunbergii targets barrier-to-autointegration factor to treat cancer.
abstract: Targeting specific molecules is a promising cancer treatment because certain types of cancer cells are dependent on specific oncogenes. This strategy led to the development of therapeutics that use monoclonal antibodies or small-molecule inhibitors. However, the continued development of novel molecular targeting inhibitors is required to target the various oncogenes associated with the diverse types and stages of cancer. Obtusilactone B is a butanolide derivative purified from Machilus thunbergii. In this study, we show that obtusilactone B functions as a small-molecule inhibitor that causes abnormal nuclear envelope dynamics and inhibits growth by suppressing vaccinia-related kinase 1 (VRK1)-mediated phosphorylation of barrier-to-autointegration factor (BAF). BAF is important in maintaining lamin integrity, which is closely associated with diseases that include cancer. Specific binding of obtusilactone B to BAF suppressed VRK1-mediated BAF phosphorylation and the subsequent dissociation of the nuclear envelope from DNA that allows cells to progress through the cell cycle. Obtusilactone B potently induced tumor cell death in vitro, indicating that specific targeting of BAF to block cell cycle progression can be an effective anticancer strategy. Our results demonstrate that targeting a major constituent of the nuclear envelope may be a novel and promising alternative approach to cancer treatment.
authors.affiliation: Department of Life Science, Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang, Republic of Korea.
authors.forename: Wanil
authors.initials: W
authors.lastname: Kim
authors.forename: Ha-Na
authors.initials: HN
authors.lastname: Lyu
authors.forename: Hyun-Sook
authors.initials: HS
authors.lastname: Kwon
authors.forename: Ye Seul
authors.initials: YS
authors.lastname: Kim
authors.forename: Kyung-Ha
authors.initials: KH
authors.lastname: Lee
authors.forename: Do-Yeon
authors.initials: DY
authors.lastname: Kim
authors.forename: Goutam
authors.initials: G
authors.lastname: Chakraborty
authors.forename: Kwan Yong
authors.initials: KY
authors.lastname: Choi
authors.forename: Ho Sup
authors.initials: HS
authors.lastname: Yoon
authors.forename: Kyong-Tai
authors.initials: KT
authors.lastname: Kim
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D009685:Nuclear Envelope / Q000187:drug effects* / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D018547:Plant Stems / Q000737:chemistry; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C501959:BANF1 protein, human; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D010936:Plant Extracts; D004247:DNA; D017346:Protein Serine-Threonine Kinases; C109890:VRK1 protein, human