Oncogene, 2002-05, Vol.21 (20), p.3162-3171
2002
Details
- Autor(en) / Beteiligte
- Titel
- Downregulation of human polo-like kinase activity by antisense oligonucleotides induces growth inhibition in cancer cells
- Ist Teil von
- Oncogene, 2002-05, Vol.21 (20), p.3162-3171
- Ort / Verlag
- Basingstoke: Nature Publishing
- Erscheinungsjahr
- 2002
- Link zum Volltext
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- A central role for polo-like kinases (PLK) in regulating several stages of mitotic progression has been born out in several species. Overexpression of PLK1 is observed in the majority of hitherto analysed human tumors. PLK1 overexpression is a negative prognostic factor in patients suffering from non-small cell lung cancer, head and neck tumors, esophageal carcinomas and melanomas. In order to define the role of PLK1 for mitotic progression of human cells and for neoplastic cell growth, phosphorothioate antisense oligonucleotides (ASOs) were tested to selectively downregulate PLK1 expression in MDA-MB-435 (breast cancer), HeLa S3 (cervical carcinoma) and A549 (non-small cell lung cancer) cells. ASOs were identified which suppress PLK1 mRNA and protein in a dose-dependent and sequence-specific manner. This approach also led to reduced PLK1 serine/threonine kinase activity. Downregulation of cellular PLK1 levels in cancer cells altered cell cycle progression moderately with an elevated percentage (20-30%) of cells in G(2)/M. Furthermore, cells with reduced PLK1 protein gained a rounded phenotype with multiple centrosomes. Moreover, ASO treatment resulted in potent antiproliferative effects in cell culture. Considerable antitumor activity was observed in vivo against A549 cells. This study suggests that antisense inhibitors targeted against PLK1 at well tolerated doses may be considered as a cancer therapeutic agent.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0950-9232eISSN: 1476-5594DOI: 10.1038/sj.onc.1205412Titel-ID: cdi_proquest_journals_2641313984
- Format
- –
- Schlagworte
- Adenocarcinoma - enzymology, Adenocarcinoma - pathology, Antineoplastic Agents - pharmacology, Antisense oligonucleotides, Antitumor activity, Biological and medical sciences, Biotechnology, Breast cancer, Breast Neoplasms - enzymology, Breast Neoplasms - pathology, Carcinoma, Non-Small-Cell Lung - enzymology, Carcinoma, Non-Small-Cell Lung - pathology, Cell culture, Cell cycle, Cell Cycle - drug effects, Cell Cycle Proteins, Cell Division, Centrosomes, Cervical carcinoma, Dose-Response Relationship, Drug, Enzyme Induction, Esophageal carcinoma, Esophagus, Fundamental and applied biological sciences. Psychology, Gene Expression Regulation, Enzymologic - drug effects, Gene Expression Regulation, Neoplastic - drug effects, Gene therapy, Head and neck cancer, Head and neck carcinoma, Health. Pharmaceutical industry, HeLa Cells - drug effects, HeLa Cells - enzymology, Humans, Industrial applications and implications. Economical aspects, Kinases, Lung cancer, Lung Neoplasms - enzymology, Lung Neoplasms - pathology, Mitosis - drug effects, mRNA, Neoplasm Proteins - biosynthesis, Neoplasm Proteins - genetics, Neoplasm Proteins - physiology, Non-small cell lung carcinoma, Oligonucleotides, Antisense - administration & dosage, Oligonucleotides, Antisense - pharmacology, Phenotypes, Phosphorothioate, Plk1 protein, Polo-like kinase, Polo-Like Kinase 1, Protein Kinases - biosynthesis, Protein Kinases - genetics, Protein Kinases - physiology, Protein Serine-Threonine Kinases, Protein-serine/threonine kinase, Proto-Oncogene Proteins, RNA, Messenger - biosynthesis, RNA, Neoplasm - biosynthesis, Small cell lung carcinoma, Thionucleotides - administration & dosage, Thionucleotides - pharmacology, Threonine, Tumor Cells, Cultured - drug effects, Tumor Cells, Cultured - enzymology, Tumors