title: Polo-like kinase 1 is a potential therapeutic target in human melanoma.
abstract: Exploration of the human melanoma cell-cycle pathway can lead to identification of new therapeutic targets. By gene set enrichment analysis, we identified the cell-cycle pathway and its member polo-like kinase 1 (Plk-1) to be significantly overexpressed in primary melanomas and in melanoma metastases. In vitro expression of Plk-1 was peaked at the G2/M phase of the cell cycle. Plk-1 knockdown/inhibition led to induction of apoptosis, which was caspase-3/8-dependent and p53-independent, and involved BID and Bcl-2 proteins. Comparative genomic hybridization/single-nucleotide polymorphism arrays showed no genetic alteration in the Plk-1 locus. Previous suggestions and significant enrichment of the mitogen-activated protein kinase (MAPK) signaling pathway pointed to potential regulation of Plk-1 by MAPK signaling. Inhibition of this pathway resulted in decreased Plk-1 expression as a consequence of G1 cell-cycle arrest rather than direct regulation of Plk-1. Inhibition of MAPK and Plk-1 had an additive effect on reduced cell viability. This study shows that in human melanoma, Plk-1 expression is dynamically regulated during the cell cycle, knockdown of Plk-1 leads to apoptotic cell death, and that a combination of Plk-1 and MAPK inhibition has an additive effect on melanoma cell viability. We conclude that combined inhibition of Plk-1 and MAPK could be a potentially attractive strategy in melanoma therapy.
authors.affiliation: Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, Vienna, Austria. ahmad.jalili@meduniwien.ac.at
authors.forename: Ahmad
authors.initials: A
authors.lastname: Jalili
authors.forename: Anna
authors.initials: A
authors.lastname: Moser
authors.forename: Mikhail
authors.initials: M
authors.lastname: Pashenkov
authors.forename: Christine
authors.initials: C
authors.lastname: Wagner
authors.forename: Gaurav
authors.initials: G
authors.lastname: Pathria
authors.forename: Viola
authors.initials: V
authors.lastname: Borgdorff
authors.forename: Melanie
authors.initials: M
authors.lastname: Gschaider
authors.forename: Georg
authors.initials: G
authors.lastname: Stingl
authors.forename: Sridhar
authors.initials: S
authors.lastname: Ramaswamy
authors.forename: Stephan N
authors.initials: SN
authors.lastname: Wagner
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D016193:G1 Phase / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D023281:Genomics; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008545:Melanoma / Q000235:genetics* / Q000556:secondary / Q000628:therapy*; D009508:Nevus, Pigmented / Q000235:genetics / Q000473:pathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology*; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D000097869:Polo-Like Kinase 1; C495901:TP53 protein, human; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one