title: Cardiac glycosides block cancer growth through HIF-1α- and NF-κB-mediated Plk1.
abstract: Cardiac glycosides as inhibitors of the sodium/potassium adenosine triphosphatase (sodium pump) have been reported to block cancer growth by inducing G2/M phase arrest in many cancer cells. However, no detailed studies have been performed to distinguish between these two phases of cardiac glycoside-arrested cells. Furthermore, the underlying mechanisms involved in this cell cycle arrest process are still not known. Here, we report that bufalin and other cardiac glycosides potently induce mitotic arrest by the downregulation of polo-like kinase 1 (Plk1) expression. Live-cell imaging results demonstrate that bufalin-treated cells exhibit a marked delay in entering prophase at an early stage and are then arrested at prometaphase or induced entry into apoptosis. This phenotypic change is attributed to the downregulation of Plk1. We also show that bufalin and the knockdown of sodium pump reduce Plk1, at least in part, through downregulation of the nuclear transcription factors, hypoxia-inducible factor-1α (HIF-1α) and nuclear factor-kappa B (NF-κB). These findings suggest that cardiac glycosides induce mitotic arrest and apoptosis through HIF-1α- and NF-κB-mediated downregulation of Plk1 expression, demonstrating that HIF-1α and NF-κB are critical targets of cardiac glycosides in exerting their anticancer action.
authors.affiliation: School of Biomedical Sciences, Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China.
authors.forename: Chuan-Ming
authors.initials: CM
authors.lastname: Xie
authors.forename: Xiao-Yu
authors.initials: XY
authors.lastname: Liu
authors.forename: Sidney
authors.initials: S
authors.lastname: Yu
authors.forename: Christopher H K
authors.initials: CH
authors.lastname: Cheng
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002301:Cardiac Glycosides / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D016195:G2 Phase / Q000187:drug effects / Q000235:genetics; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008870:Microtubules / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D049468:Prometaphase / Q000187:drug effects / Q000235:genetics; D011418:Prophase / Q000187:drug effects / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D000097869:Polo-Like Kinase 1
chemical_list: D002301:Cardiac Glycosides; D018797:Cell Cycle Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1; C497442:HIF1A protein, human