Proceedings of the National Academy of Sciences - PNAS, 2011-04, Vol.108 (17), p.7177-7182
2011
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- Autor(en) / Beteiligte
- Titel
- Targeting p21-activated kinase 1 (PAK1) to induce apoptosis of tumor cells
- Ist Teil von
- Proceedings of the National Academy of Sciences - PNAS, 2011-04, Vol.108 (17), p.7177-7182
- Ort / Verlag
- United States: National Academy of Sciences
- Erscheinungsjahr
- 2011
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- p21-activated kinases (PAKs) are serine/threonine protein kinases that serve as important mediators of Rac and Cdc42 GTPase function as well as pathways required for Ras-driven tumorigenesis. PAK1 has been implicated in signaling by growth factor receptors and morphogenetic processes that control cell polarity, invasion, and actin cytoskeleton organization. To better understand the role of PAK1 in tumorigenesis, PAK1 genomic copy number and expression were determined for a large panel of breast, lung, and head and neck tumors. PAK1 genomic amplification at 11q13 was prevalent in luminal breast cancer, and PAK1 protein expression was associated with lymph node metastasis. Breast cancer cells with PAK1 genomic amplification rapidly underwent apoptosis after inhibition of this kinase. Strong nuclear and cytoplasmic PAK1 expression was also prevalent in squamous nonsmall cell lung carcinomas (NSCLCs), and selective PAK1 inhibition was associated with delayed cell-cycle progression in vitro and in vivo. NSCLC cells were profiled using a library of pathway-targeted small-molecule inhibitors, and several synergistic combination therapies, including combination with antagonists of inhibitor of apoptosis proteins, were revealed for PAK1. Dual inhibition of PAK1 and X chromosome-linked inhibitor of apoptosis efficiently increased effector caspase activation and apoptosis of NSCLC cells. Together, our results provide evidence for dysregulation of PAK1 in breast and squamous NSCLCs and a role for PAK1 in cellular survival and proliferation in these indications.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0027-8424eISSN: 1091-6490DOI: 10.1073/pnas.1103350108Titel-ID: cdi_crossref_primary_10_1073_pnas_1103350108
- Format
- –
- Schlagworte
- Actin, Animals, Antagonists, Antineoplastic Combined Chemotherapy Protocols - pharmacology, Apoptosis, Apoptosis - drug effects, Apoptosis Regulatory Proteins - antagonists & inhibitors, Biological Sciences, Breast cancer, breast neoplasms, carcinogenesis, Caspase, caspases, Caspases - metabolism, Cdc42 protein, cell cycle, Cell Cycle - drug effects, Cell growth, Cell lines, cell polarity, Cell survival, Cell Survival - drug effects, Cellular biology, copy number, Cytoskeleton, Drug Delivery Systems, Enzyme Activation - drug effects, Epithelial cells, Female, Gene expression, Gene expression regulation, Gene Expression Regulation, Neoplastic - drug effects, Genomics, Growth factor receptors, Guanosinetriphosphatase, head, Head and neck, Humans, Kinases, Lung carcinoma, lung neoplasms, Lymph nodes, Lymph Nodes - enzymology, Lymph Nodes - pathology, Lymphatic Metastasis, Male, Metastases, Metastasis, Mice, Mice, Nude, microfilaments, neck, neoplasm cells, Neoplasm Proteins - antagonists & inhibitors, Neoplasm Proteins - metabolism, Neoplasms - drug therapy, Neoplasms - enzymology, Neoplasms - pathology, Non small cell lung carcinoma, p21-activated kinase, p21-activated kinase 1, p21-Activated Kinases - antagonists & inhibitors, p21-Activated Kinases - metabolism, Polarity, Protein kinase, Protein Kinase Inhibitors - pharmacokinetics, protein synthesis, protein-serine-threonine kinases, receptors, Serine, Signal transduction, Threonine, Tumor cell line, Tumor cells, Tumorigenesis, Tumors