Targeting p21-activated kinase 1 (PAK1) to induce apoptosis of tumor cells
- 11 April 2011
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 108 (17), 7177-7182
- https://doi.org/10.1073/pnas.1103350108
Abstract
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.Keywords
This publication has 41 references indexed in Scilit:
- Active p21-Activated Kinase 1 Rescues MCF10A Breast Epithelial Cells from Undergoing AnoikisNeoplasia, 2005
- Rational design and characterization of a Rac GTPase-specific small molecule inhibitorProceedings of the National Academy of Sciences of the United States of America, 2004
- p21-activated Kinase-1 Signaling Mediates Cyclin D1 Expression in Mammary Epithelial and Cancer CellsPublished by Elsevier BV ,2004
- Combined Array Comparative Genomic Hybridization and Tissue Microarray Analysis Suggest PAK1 at 11q13.5-q14 as a Critical Oncogene Target in Ovarian CarcinomaThe American Journal of Pathology, 2003
- p38 Mitogen-Activated Protein Kinase Mediates Cell Death and p21-Activated Kinase Mediates Cell Survival during Chemotherapeutic Drug-induced Mitotic ArrestMolecular Biology of the Cell, 2003
- E2F integrates cell cycle progression with DNA repair, replication, and G2/M checkpointsGenes & Development, 2002
- Regulatable Expression of p21-activated Kinase-1 Promotes Anchorage-independent Growth and Abnormal Organization of Mitotic Spindles in Human Epithelial Breast Cancer CellsPublished by Elsevier BV ,2000
- p21-Activated Kinase 1 Phosphorylates the Death Agonist Bad and Protects Cells from ApoptosisMolecular and Cellular Biology, 2000
- Human p21-activated kinase (Pak1) regulates actin organization in mammalian cellsCurrent Biology, 1997
- Amplification of chromosome band 11q13 and a role for cyclin D1 in human breast cancerCancer Letters, 1995